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

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 9.60

Variant links:

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]

TYRP1 links:

LURAP1L-AS1 (HGNC:49761): (LURAP1L antisense RNA 1)

LURAP1L-AS1 links:

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
TYRP1	NM_000550.3 linkuse as main transcript	c.1067G>A	p.Arg356Gln	missense_variant	5/8	ENST00000388918.10
LURAP1L-AS1	NR_125775.1 linkuse as main transcript	n.317-1798C>T		intron_variant, non_coding_transcript_variant
TYRP1	XM_047423841.1 linkuse as main transcript	c.862G>A	p.Glu288Lys	missense_variant	4/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TYRP1	ENST00000388918.10 linkuse as main transcript	c.1067G>A	p.Arg356Gln	missense_variant	5/8	1	NM_000550.3	P1
LURAP1L-AS1	ENST00000417638.1 linkuse as main transcript	n.273-1798C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes

AF:

0.0000395

AC:

AN:

151960

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.000480

GnomAD3 exomes

AF:

0.0000279

AC:

AN:

250454

Hom.:

AF XY:

0.0000369

AC XY:

AN XY:

135334

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000981

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000354

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000411

AC:

AN:

1460568

Hom.:

Cov.:

AF XY:

0.0000427

AC XY:

AN XY:

726600

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000928

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000459

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000395

AC:

AN:

151960

Hom.:

Cov.:

AF XY:

0.0000270

AC XY:

AN XY:

74198

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.000480

Alfa

AF:

0.0000819

Hom.:

Bravo

AF:

0.0000453

ExAC

AF:

0.0000247

AC:

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: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.89

BayesDel_addAF

Pathogenic

0.42

BayesDel_noAF

Pathogenic

0.57

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.83

D;.

Eigen

Pathogenic

0.90

Eigen_PC

Pathogenic

0.86

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

D;D

M_CAP

Uncertain

0.28

MetaRNN

Pathogenic

0.89

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.6

H;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.50

PROVEAN

Uncertain

-2.8

D;D

REVEL

Pathogenic

0.90

Sift

Uncertain

0.0020

D;D

Sift4G

Uncertain

0.0040

D;D

Polyphen

0.99

D;.

Vest4

0.92

MutPred

0.60

Loss of catalytic residue at R356 (P = 0.0446);.;

MVP

1.0

MPC

0.025

ClinPred

0.94

GERP RS

5.7

Varity_R

0.94

gMVP

0.93

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over