chr11-89178528-C-A
Variant summary
Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1
The NM_000372.5(TYR):c.575C>A(p.Ser192Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.314 in 1,613,856 control chromosomes in the GnomAD database, including 90,450 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000372.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -12 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.242 AC: 36804AN: 151964Hom.: 6055 Cov.: 32
GnomAD3 exomes AF: 0.254 AC: 63923AN: 251456Hom.: 10823 AF XY: 0.261 AC XY: 35434AN XY: 135900
GnomAD4 exome AF: 0.322 AC: 470738AN: 1461774Hom.: 84395 Cov.: 40 AF XY: 0.319 AC XY: 231839AN XY: 727190
GnomAD4 genome AF: 0.242 AC: 36791AN: 152082Hom.: 6055 Cov.: 32 AF XY: 0.231 AC XY: 17181AN XY: 74342
ClinVar
Submissions by phenotype
Oculocutaneous albinism type 1A Uncertain:1Benign:3Other:1
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This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PS3,PP3,PP4,BP6,BS1,BA1. -
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not specified Uncertain:1Benign:2
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Variant summary: TYR c.575C>A (p.Ser192Tyr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.25 in 251456 control chromosomes in the gnomAD database, including 10823 homozygotes. The observed variant frequency is approximately 45-fold of the estimated maximal expected allele frequency for a pathogenic variant in TYR causing Oculocutaneous Albinism phenotype (0.0056), strongly suggesting that the variant is benign. c.575C>A has been reported in the literature in individuals affected with Oculocutaneous Albinism and nystagmus without strong evidence of causality (Wei_2015, Thomas_2017). These reports do not provide unequivocal conclusions about association of the variant with Oculocutaneous Albinism. At least two publications report experimental evidence evaluating an impact on protein function, showing ~60% of wildtype enzymatic activity and a reduction in pigment production in cells with the variant construct. Seven submitters have submitted clinical-significance assessments for this variant to ClinVar after 2014, and reported the variant with conflicting assessments (four as benign, one as VUS, one as pathogenic, and one as association). Based on the evidence outlined above, the variant was classified as likely benign. -
This variant is very common in the general population, being documented in 45% of alleles in individuals of Ashkenazi Jewish descent (http://gnomad.broadinstitute.org/variant/11-88911696-C-A). Given the high allele frequency, including thousands of homozygotes this variant is not considered pathogenic individually. However, when this variant is in cis (present in the same copy of TYR) with the variant c.1205G>A (p.Arg402Gln), there is strong evidence that they create a pathogenic allele. Functional and phenotypic studies of the complex allele (p.[Arg402Gln;Ser192Tyr]; commonly referred to as a haplotype in the literature) indicate that the two substitutions have a compound effect on thermal stability of the protein and phenotypic spectrum of the individual (Tripathi et al. 1991. PubMed ID: 1820207; Chaki et al. 2011. PubMed ID: 20861851; Jagirdar et al. 2014. PubMed ID: 24739399). The p.[Arg402Gln;Ser192Tyr] allele is thought to be a recombination of the two individual variant alleles and is reported in ~1-2% of alleles (Jagirdar et al. 2014. PubMed ID: 24739399; Norman et al. 2017. PubMed ID: 28667292). However, this complex allele is enriched (up to 20%) in OCA patients with only one previously identified pathogenic variant in TYR (Lasseaux et al. 2018. PubMed ID: 29345414; Grønskov et al. 2019. PubMed ID: 30679655; Campbell et al. 2019. PubMed ID: 31719542). Given the evidence, we interpret the p.[Arg402Gln;Ser192Tyr] allele as likely pathogenic. When it is unclear whether the c.575C>A (p.Ser192Tyr) variant is part of the complex allele or not, then the clinical significance of it is uncertain. -
not provided Benign:2Other:1
TYR: BP4, BS1, BS2 -
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SKIN/HAIR/EYE PIGMENTATION 3, LIGHT/DARK SKIN Pathogenic:1Other:1
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Oculocutaneous albinism Uncertain:1Benign:1
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
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Oculocutaneous albinism type 1B Pathogenic:1
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Albinism or congenital nystagmus Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at