rs761776915
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Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate
The NM_000550.3(TYRP1):āc.1354A>Gā(p.Met452Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000166 in 1,612,750 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ).
Frequency
Genomes: š 0.00012 ( 0 hom., cov: 33)
Exomes š: 0.00017 ( 1 hom. )
Consequence
TYRP1
NM_000550.3 missense
NM_000550.3 missense
Scores
7
5
7
Clinical Significance
Conservation
PhyloP100: 8.95
Genes affected
TYRP1 (HGNC:12450): (tyrosinase related protein 1) This gene encodes a melanosomal enzyme that belongs to the tyrosinase family and plays an important role in the melanin biosynthetic pathway. Defects in this gene are the cause of rufous oculocutaneous albinism and oculocutaneous albinism type III. [provided by RefSeq, Mar 2009]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 4 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.842
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TYRP1 | NM_000550.3 | c.1354A>G | p.Met452Val | missense_variant | 7/8 | ENST00000388918.10 | |
LURAP1L-AS1 | NR_125775.1 | n.317-7463T>C | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TYRP1 | ENST00000388918.10 | c.1354A>G | p.Met452Val | missense_variant | 7/8 | 1 | NM_000550.3 | P1 | |
LURAP1L-AS1 | ENST00000417638.1 | n.273-7463T>C | intron_variant, non_coding_transcript_variant | 3 |
Frequencies
GnomAD3 genomes ? AF: 0.000118 AC: 18AN: 152014Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000439 AC: 11AN: 250384Hom.: 0 AF XY: 0.0000517 AC XY: 7AN XY: 135348
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GnomAD4 exome AF: 0.000171 AC: 250AN: 1460736Hom.: 1 Cov.: 31 AF XY: 0.000168 AC XY: 122AN XY: 726682
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GnomAD4 genome ? AF: 0.000118 AC: 18AN: 152014Hom.: 0 Cov.: 33 AF XY: 0.000108 AC XY: 8AN XY: 74236
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Dec 13, 2016 | - - |
Oculocutaneous albinism type 3 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | 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. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 22, 2022 | This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 452 of the TYRP1 protein (p.Met452Val). This variant is present in population databases (rs761776915, gnomAD 0.008%). This missense change has been observed in individual(s) with clinical features of ocular albinism (PMID: 18326704). This variant is also known as c.1351A>G (p.Met451Val). ClinVar contains an entry for this variant (Variation ID: 437184). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D
MetaSVM
Pathogenic
D
MutationAssessor
Uncertain
M;.
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N
REVEL
Pathogenic
Sift
Benign
T;T
Sift4G
Benign
T;T
Polyphen
D;.
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at