rs281865424
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PP3_ModeratePP5_Very_Strong
The NM_000550.3(TYRP1):c.1067G>A(p.Arg356Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000409 in 1,612,528 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000041 ( 0 hom. )
Consequence
TYRP1
NM_000550.3 missense
NM_000550.3 missense
Scores
13
5
1
Clinical Significance
Conservation
PhyloP100: 9.60
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 14 ACMG points.
PM1
?
In a helix (size 5) in uniprot entity TYRP1_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_000550.3
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.894
PP5
?
Variant 9-12702424-G-A is Pathogenic according to our data. Variant chr9-12702424-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 17596.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-12702424-G-A is described in Lovd as [Pathogenic]. Variant chr9-12702424-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TYRP1 | NM_000550.3 | c.1067G>A | p.Arg356Gln | missense_variant | 5/8 | ENST00000388918.10 | |
LURAP1L-AS1 | NR_125775.1 | n.317-1798C>T | intron_variant, non_coding_transcript_variant | ||||
TYRP1 | XM_047423841.1 | c.862G>A | p.Glu288Lys | missense_variant | 4/5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TYRP1 | ENST00000388918.10 | c.1067G>A | p.Arg356Gln | missense_variant | 5/8 | 1 | NM_000550.3 | P1 | |
LURAP1L-AS1 | ENST00000417638.1 | n.273-1798C>T | intron_variant, non_coding_transcript_variant | 3 |
Frequencies
GnomAD3 genomes ? AF: 0.0000395 AC: 6AN: 151960Hom.: 0 Cov.: 32
GnomAD3 genomes
?
AF:
AC:
6
AN:
151960
Hom.:
Cov.:
32
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.0000279 AC: 7AN: 250454Hom.: 0 AF XY: 0.0000369 AC XY: 5AN XY: 135334
GnomAD3 exomes
AF:
AC:
7
AN:
250454
Hom.:
AF XY:
AC XY:
5
AN XY:
135334
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.0000411 AC: 60AN: 1460568Hom.: 0 Cov.: 30 AF XY: 0.0000427 AC XY: 31AN XY: 726600
GnomAD4 exome
AF:
AC:
60
AN:
1460568
Hom.:
Cov.:
30
AF XY:
AC XY:
31
AN XY:
726600
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome ? AF: 0.0000395 AC: 6AN: 151960Hom.: 0 Cov.: 32 AF XY: 0.0000270 AC XY: 2AN XY: 74198
GnomAD4 genome
?
AF:
AC:
6
AN:
151960
Hom.:
Cov.:
32
AF XY:
AC XY:
2
AN XY:
74198
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Alfa
AF:
Hom.:
Bravo
AF:
ExAC
?
AF:
AC:
3
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Oculocutaneous albinism type 3;C2677086:Skin/hair/eye pigmentation, variation in, 11 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Feb 24, 2022 | - - |
Oculocutaneous albinism type 3 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 01, 2006 | - - |
Nonsyndromic Oculocutaneous Albinism Pathogenic:1
Likely pathogenic, no assertion criteria provided | research | University of Washington Center for Mendelian Genomics, University of Washington | Mar 07, 2017 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 19, 2024 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 356 of the TYRP1 protein (p.Arg356Gln). This variant is present in population databases (rs281865424, gnomAD 0.01%). This missense change has been observed in individuals with oculocutaneous albinism (PMID: 16704458, 21739261, 28266639). This variant is also known as c.1066G>A. ClinVar contains an entry for this variant (Variation ID: 17596). 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 TYRP1 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. - |
TYRP1-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | May 30, 2023 | The TYRP1 c.1067G>A variant is predicted to result in the amino acid substitution p.Arg356Gln. This variant has been reported in the homozygous and compound heterozygous state in individuals with oculocutaneous albinism (Rooryck et al. 2006. PubMed ID: 16704458; Shahzad et al. 2017. PubMed ID: 28266639; Zhang et al. 2011. PubMed ID: 21739261). This variant is reported in 0.0098% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/9-12702424-G-A). Given the evidence, we interpret c.1067G>A (p.Arg356Gln) as pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Pathogenic
D;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H;.
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D
REVEL
Pathogenic
Sift
Uncertain
D;D
Sift4G
Uncertain
D;D
Polyphen
D;.
Vest4
MutPred
Loss of catalytic residue at R356 (P = 0.0446);.;
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at