hu76CAA5 - GET-Evidence variant report

Variant report for hu76CAA5

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VariantClinical
Importance
ImpactAllele
freq
Summary
1SIAE-M89VModerateUncertainUncertain pathogenic

Recessive, Carrier (Heterozygous)
0.0400632This variant was reported to be associated with autoimmune disease when homozygous. However, a later publication has contradicted this result, finding no significant association between this variant and autoimmune disease in a very large cohort.1
2MTRR-I49MLowLikelyLikely pathogenic

Recessive, Homozygous
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
3rs5186LowLikelyLikely 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
4AMPD1-Q12XLowLikelyLikely pathogenic

Recessive, Carrier (Heterozygous)
0.0930643Causes Adenosine Deaminase Deficiency in a recessive manner. Most of the time individuals do not report symptoms, but when symptoms do exist they to be post-exercise symptoms of muscle weakness, muscle pain, and getting tired more quickly.1
5TP53-P72RLowUncertainUncertain pathogenic

Unknown, Heterozygous
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
6HFE-H63DLowUncertainUncertain pathogenic

Recessive, Carrier (Heterozygous)
0.109965There have been some hypotheses that this variant contributes to causing hereditary hemochromatosis, possibly as a compound heterozygote, but some others treat it as a polymorphism. Cys282Tyr is the classic causal variant and itself has very low penetrance. Mouse studies indicates this variant has a similar but weaker effect; if it has any effect at all its penetrance may be quite low and/or require modifier alleles.1
7SP110-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
8H6PD-R453QLowUncertainUncertain pathogenic

Recessive, Carrier (Heterozygous)
0.308886This common variant may have a small pathogenic effect by contributing to cortisone reductase deficiency (a rare abnormality) when homozygous and combined with a serious pathogenic variant. The same authors have tested and ruled out a contribution to polycystic ovary syndrome (similar phenotype, more common disease).1
9FUT2-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
10NPC1-H215RLowLikelyLikely protective

Complex/Other, Heterozygous
0.295687This variant is associated with a reduced risk of obesity, with an additive effect of -0.084 BMI per allele (an average of 0.54 pounds less, per allele, in a 5'6" individual). 1
11DTNBP1-P272SLowUncertainUncertain protective

Recessive, Carrier (Heterozygous)
0.0351366Possibly a slight protective effect against colorectal cancer if homozygous.1
12PKD1-A4059VLowLikelyLikely benign

Unknown, Heterozygous
0.0570413Probably benign.1
13RYR2-G1885ELowLikelyLikely benign

Recessive, Carrier (Heterozygous)
0.0179176Hypothesized to cause arrhythmogenic right ventricular cardiomyopathy when compound heterozygous with G1886S. However, this variant is quite common (2.4% in Europeans), as is G1886S (3.1% in Europeans), and about 1 in 700 are compound heterozygous. This is highly discordant with a disease prevalence of 1 in 2500 to 5000, and notably G1886S is reported in ClinVar as benign. We should consider the original hypothesis disproven.1
14FANCI-P55LLowLikelyLikely benign

Unknown, Heterozygous
0.0507529Probably benign.1
15COL6A3-D2831HLowLikelyLikely benign

Unknown, Heterozygous
0.0678565Probably benign, reported by Pan et al. as a presumed-nonpathogenic variant in the gene.1
16OCA2-R419QLowLikelyLikely benign

Unknown, Heterozygous
0.0565161This variant is associated with eye color, as is OCA2 R305W. Individuals with this variant are reported to be more likely to have green/hazel eyes as opposed to blue/gray eyes. Other variants in this gene are associated with oculocutaneous albinism (albinism which involves skin and eyes).1
17MLH1-I219VLowUncertainUncertain benign

Dominant, Heterozygous
0.239822Computational evidence, functional assays, and case/control studies suggest this variant is probably benign.1
18KEL-T193MLowUncertainUncertain benign

Dominant, Heterozygous
0.0320692This variant is also known as Kell or K1 or K (capitalized) in the Kell antigen system. K1-negative mothers (carrying no copies of this variant) carrying K1-positive fetuses (heterozygous or homozygous) are at risk for hemolytic disease of the newborn. About 9% of caucasians carry one or two copies of K1.1
19COL4A4-G999ELowUncertainUncertain benign

Dominant, Heterozygous
0.0100948This variant is causative for Benign Familial Hematuria (thin membrane basement disease). While this variant is benign, it is useful in differentiating glomerular hematuria from Alport Syndrome.1
20RPGRIP1-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
21TCIRG1-R56WLowUncertainUncertain benign

Unknown, Heterozygous
0.0441778Probably benign. One publication implicates the variant in causing osteopetrosis, but this is contradicted by the relatively high allele frequency for the variant in Caucasians (5%, 1 in 400 homozygous) while that disease is extremely rare (1 in 250,000).1
22GALT-N314DLowUncertainUncertain benign

Unknown, Heterozygous
0.0716676This variant has an allele frequency of ~8% and is ancestral to "Duarte" / "Duarte 2" and "Duarte 1"/"Los Angeles" galactosemia variants. This variant is evolutionarily ancestral, and in vitro studies fail to support an impact of this variant on enzyme activity. Carney et al. instead implicate a 4 base deletion on the 5' of the GALT gene as being causal and linked to this variant. Galactosemia is typically screened and detected in infants and causes early, severe but nonspecific symptoms (digestive problems, lethargy, failure to thrive).1
23PHYH-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
24APOB-Y1422CLowUncertainUncertain benign

Unknown, Homozygous
0.999628This position is almost certainly an error in the HG18 reference sequence. 1
25AMPD1-P48LLowUncertainUncertain benign

Unknown, Heterozygous
0.0940695Probably benign, ancestral to15173240 pathogenic Q12X mutation.1
26PCSK9-G670ELowUncertainUncertain benign

Unknown, Homozygous
0.888269This variant is likely benign. 1
27PTCH1-P1315LLowUncertainUncertain benign

Unknown, Homozygous
0.29631Common polymorphism, presumed benign.1
28RP1-N985YLowUncertainUncertain benign

Unknown, Homozygous
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

Gene search

"GENE" or "GENE A123C":

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