rs142170797
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BS2_Supporting
The NM_000372.5(TYR):c.915C>A(p.Asp305Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000348 in 1,613,694 control chromosomes in the GnomAD database, including 3 homozygotes. 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 Likely_benign. Variant got -1 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000210 AC: 32AN: 152068Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000299 AC: 75AN: 251188Hom.: 0 AF XY: 0.000324 AC XY: 44AN XY: 135742
GnomAD4 exome AF: 0.000363 AC: 531AN: 1461508Hom.: 3 Cov.: 31 AF XY: 0.000406 AC XY: 295AN XY: 727046
GnomAD4 genome AF: 0.000204 AC: 31AN: 152186Hom.: 0 Cov.: 32 AF XY: 0.000215 AC XY: 16AN XY: 74412
ClinVar
Submissions by phenotype
not provided Uncertain:3
In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26764160, 34426522, 30868138, 21906913, 19060277, 34008892, 30679655, 27734839, 13680365) -
This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 305 of the TYR protein (p.Asp305Glu). This variant is present in population databases (rs142170797, gnomAD 0.04%). This missense change has been observed in individual(s) with clinical features of ocular albinism (PMID: 13680365, 19060277, 27734839, 34008892). ClinVar contains an entry for this variant (Variation ID: 418532). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TYR protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
TYR: PM5, PM2:Supporting -
Oculocutaneous albinism type 1A Pathogenic:1Uncertain:1
PS4,PM1,PP2,PP3 -
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not specified Uncertain:1
Variant summary: TYR c.915C>A (p.Asp305Glu) results in a conservative amino acid change located in the copper-binding domain (IPR002227) of 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 0.00034 in 1606724 control chromosomes in the gnomAD database, including 3 homozygotes. This frequency is not higher than the estimated maximum expected for a pathogenic variant in TYR causing Oculocutaneous Albinism (0.0056), allowing no conclusion about variant significance. c.915C>A has been reported in the literature in compound heterozygous state together with a second pathogenic variant, in an affected individual (with dermatological abnormalities), however no further phenotype details were provided (Marinakis_2021). In addition, the variant was also reported in heterozygous state in individuals affected with Oculocutaneous Albinism in whom a second (likely) pathogenic mutation was not identified (e.g. King_2003, Gronskov_2009, Mauri_2016), and was also reported in unaffected controls (Hu_011, Dopazo_2016). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 13680365, 19060277, 21906913, 27734839, 26764160, 34008892). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance. -
Oculocutaneous albinism Uncertain:1
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Oculocutaneous albinism type 1B;C2677190:SKIN/HAIR/EYE PIGMENTATION 3, LIGHT/DARK SKIN;C4551504:Oculocutaneous albinism type 1A Uncertain:1
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Oculocutaneous albinism type 1B;C2677190:SKIN/HAIR/EYE PIGMENTATION 3, LIGHT/DARK SKIN;C4551504:Oculocutaneous albinism type 1A;CN028925:Ocular albinism with congenital sensorineural hearing loss Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at