hu54EA88 (My 23andme) - GET-Evidence variant report

Variant report for hu54EA88 (My 23andme)

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VariantClinical
Importance
ImpactAllele
freq
Summary
1SERPINA1-E366KHighWell-establishedWell-established pathogenic

Recessive, Carrier (Heterozygous)
0.0117122This is also called the "Pi Z" or "Z" allele. When homozygous (acting in a recessive manner) this variant is the major cause of severe alpha-1-antitrypsin deficiency (95% of cases) which often leads to emphysema or chronic obstructive pulmonary disease (COPD) and liver disease in adults and children. Heterozygosity for this variant may also be associated with increased rate of lung or liver problems, especially when combined with another variant with reduced function (compound heterozygous).1
2C3-R102GModerateLikelyLikely pathogenic

Complex/Other, Heterozygous
0.152073This variant (also called C3F) is common in Europeans (10.2% allele frequency), and is associated with age-related macular degeneration. In the US, 1.5% of adults over 40 have the disease, but the incidence increases strongly with age (>15% in women over 80). Assuming an average lifetime risk of ~10%, heterozygous individuals have a ~13% risk and homozygous have ~20%.1
3COL4A1-Q1334HLowLikelyLikely pathogenic

Dominant, Heterozygous
0.324689This common variant has been associated with arterial stiffness and, in Japanese, a small increased risk of myocardial infarction (MI, a.k.a. heart attack). This last observation supported a dominant effect for this variant and, assuming a lifetime risk of 15% for MI, we estimate carriers have an additional risk of 0.5-3%.1
4rs5186LowLikelyLikely pathogenic

Unknown, Heterozygous
0.214878This common noncoding genetic variant has an allele frequency of ~30% and is associated with an increased risk of hypertension. If ~25% of non-carriers have hypertension, Bonnardeaux et al's data predict ~4% increased risk of hypertension per copy of this variant. This SNP is in the 3' noncoding region of the AGTR1 transcript (angiotensin II type 1 receptor), also known as AT2R1 or AT1R, which is a target of hypertension drugs.1
5MBL2-R52CLowLikelyLikely pathogenic

Recessive, Carrier (Heterozygous)
0.048615This variant is associated with mannose binding protein deficiency which leads to impaired complement system immune response to mannose-rich pathogens. Patients homozygous for this allele or compound heterozygous are likely to have increased susceptibility to infection, but Hellemann et al. report heterosis for intensive care outcomes in heterozygous subjects. The wild-type version of this gene is known as variant allele A, while this is called variant allele D. See G54D (variant B) and G57E (variant C).1
6MTRR-I49MLowLikelyLikely pathogenic

Recessive, Carrier (Heterozygous)
0.451199This common variant (HapMap allele frequency of 31.3%) in a protein involved in folate (B9) and cobalamin (B12) metabolism and is often reported as "MTRR I22M" (an alternative transcript position). Mothers homozygous for this variant are associated with having around a increased chance of a child with Down syndrome (risk of 0.4%, average risk in population is 0.25%). Notably, age plays a far larger role in the rate of Down syndrome (risk is 4.5% for a mother 45-years-of-age), and it is unknown how this variant may combine with the effect of age. There are conflicting reports associating this variant with incidence of neural tube defects, possibly when combined with MTHFR A222V.1
7TGFB1-R25PLowUncertainUncertain pathogenic

Complex/Other, Heterozygous
0.0488858This variant in a growth factor gene is associated with variation in TGFB1 levels; this has been associated with various pathogenic and some protective effects, including: more hepatic fibrosis progression in hep C patients, lower risk of cleft palate, anticorrelation with longevity, higher risk of myocardial infarction and lower risk of hypertension.1
8DYX1C1-E417XLowUncertainUncertain pathogenic

Unknown, Heterozygous
0.20147One study reports this variant to be associated with dyslexia. The study group was relatively small and so the results did not have strong significance. If they are representative this variant is associated with a doubled risk for dyslexia, but it is unclear whether the effect would be additive, dominant, or recessive.1
9WFS1-R611HLowUncertainUncertain not reviewed

Recessive, Carrier (Heterozygous)
0.400446This nonsynonymous SNP is associated with Wolfram Syndrome (known as DIDMOAD), which is characterized by early-onset non-autoimmune diabetes mellitus, diabetes insipidus, optic atrophy, and deafness) and to adult Type Two Diabetes Mellitus. The WFS1 gene maps to chromosome 4p16.3. The variant has been shown to be statistically associated with type II diabetes in six UK studies and one study of Ashkenazi Jews (Sandhu, M., et al., Minton et al.).1
10SP110-L425SLowUncertainUncertain pathogenic

Unknown, Homozygous
0.863357This variant is associated with a slightly increased risk of tuberculosis. It is unclear whether it is itself causal, or in linkage disequilibrium with some other causal variant that has a stronger effect.1
11CLEC7A-Y238XLowUncertainUncertain pathogenic

Recessive, Carrier (Heterozygous)
0.0632088This variant has been found to impair homan mucosal antifungal defense and was implicated in vulvovaginal candidiasis and mucocutaneous infections in a Dutch family.1
12TP53-P72RLowUncertainUncertain pathogenic

Unknown, Homozygous
0.627743This is a common variant was first reported as a polymorphism. It has since had mixed associations with cancer: Storey et al. conclude a 7x *increased* risk of HPV cancer for homozygotes vs hets, but Jones et al. find a 1.98x *decreased* risk for colorectal cancer. This variant may have significant impact on particular cancers, but it is unclear what effect it has on the overall burden of cancer.1
13FUT2-W154XModerateWell-establishedWell-established protective

Recessive, Carrier (Heterozygous)
0.490519This recessive protective variant confers resistance to norovirus (which causes stomach flu). 20% of Caucasians and Africans are homozygous for this variant and are "non-secretors": they do not express ABO blood type antigens in their saliva or mucosal surfaces. Most strains of norovirus bind to these antigens in the gut, and so this non-secretor status confers almost total resistantance to most types of norovirus. There are notable exceptions, some strains of norovirus bind a different target and are equally infectious for secretors and non-secretors.1
14ABCG5-R50CLowLikelyLikely protective

Unknown, Heterozygous
0.0684142This variant has a mild protective effect on blood cholesterol. It is associated with slightly lower total and LDL cholesterol levels.1
15KCNJ11-K23ELowLikelyLikely protective

Unknown, Heterozygous
0.738148This variant is associated with decreased risk of type 2 diabetes. It is unclear whether this variant has additive effects, or acts in a dominant or recessive manner. Assuming diabetes has a lifetime risk of 36%, we estimate a decreased risk of around 1-2% per copy of this variant.1
16LIG4-A3VLowUncertainUncertain protective

Dominant, Heterozygous
0.035843One report has associated this with a decreased risk of multiple myeloma.1
17MTR-D919GLowUncertainUncertain protective

Complex/Other, Heterozygous
0.217234This variant was weakly associated with a protective effect vs. colorectal cancer, but only in individuals with low alcohol consumption. 1
18LPL-S474XLowUncertainUncertain protective

Unknown, Heterozygous
0.0844953This variant actually increases LPL enzyme activity despite creating a termination codon (see Rip J et al). It appears to be a protective variant, associated with lower triglyceride levels--although the effect is quite weak and explains only 0.5-1% of triglyceride variation.1
19RPGRIP1-A547SLowUncertainUncertain benign

Complex/Other, Heterozygous
0.232202Probably benign. Implicated in causing autosomal recessive cone-rod dystrophy, but a later report found the same incidence in controls and concludes it is not causal.1
20LOXL1-R141LLowUncertainUncertain benign

Complex/Other, Heterozygous
0.255899Associated with exfoliative glaucoma & syndrome (XFG & XFS) in various populations, but with contradicting results (protective in Caucasians, pathogenic in Japanese). Based on this it seems the variation itself -- although it affects protein structure -- is not itself causing disease. Instead it is likely associated with other nearby causal variants. As such, it is evaluated as benign by GET-Evidence (which focuses on reporting causal variants). See detailed variant report for disease risk associations.1
21PCCA-I475VLowUncertainUncertain benign

Unknown, Heterozygous
0.0377394Reported as a polymorphism, tentatively presumed benign.1
22TYR-S192YLowUncertainUncertain benign

Unknown, Heterozygous
0.270682This variant is reported to affect skin pigmentation. It is associated with lighter skin in South Asians (OR 4-5) and with a lack of freckles in Europeans (OR 1.3).1
23PTCH1-P1315LLowUncertainUncertain benign

Unknown, Heterozygous
0.29631Common polymorphism, presumed benign.1
24PHYH-P29SLowUncertainUncertain benign

Unknown, Heterozygous
0.155326Probably benign. This variant was implicated as causing Refsum Disease in a recessive manner, but a subsequent publication noted that all instances were linked with other explanatory mutations. The high allele frequency of this variant in the population (7-13%) contradicts a pathogenic hypothesis.1
25PCSK9-G670ELowUncertainUncertain benign

Unknown, Homozygous
0.888269This variant is likely benign. 1
26PKP2-L366PLowUncertainUncertain benign

Unknown, Heterozygous
0.221231This variant is a benign polymorphism. 1
27APOB-Y1422CLowUncertainUncertain benign

Unknown, Homozygous
0.999628This position is almost certainly an error in the HG18 reference sequence. 1
28RP1-N985YLowUncertainUncertain benign

Unknown, Heterozygous
0.348671Probably benign. One report linked this variant to high triglycerides, but a later paper found a nearby SNP with similar association and suggests that both findings are caused by linkage to an undiscovered causal variant.1
29SLC45A2-L374FLowUncertainUncertain benign

Unknown, Homozygous
0.691764Pigmentation allele for non-black hair, and consequently, possible increased susceptibility to malignant melanoma.1
VariantPrioritization scoreAllele
freq
Num of
articles
Zygosity and Prioritization Score Reasons

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"GENE" or "GENE A123C":

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