NM_000372.5:c.1265G>A

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2PM5PP3PP5_Very_Strong

The NM_000372.5(TYR):c.1265G>A(p.Arg422Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000366 in 1,611,886 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R422W) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000038 ( 0 hom. )

Consequence

TYR
NM_000372.5 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:7O:1

Conservation

PhyloP100: 3.51

Variant links:

Genes affected

TYR (HGNC:12442): (tyrosinase) The enzyme encoded by this gene catalyzes the first 2 steps, and at least 1 subsequent step, in the conversion of tyrosine to melanin. The enzyme has both tyrosine hydroxylase and dopa oxidase catalytic activities, and requires copper for function. Mutations in this gene result in oculocutaneous albinism, and nonpathologic polymorphisms result in skin pigmentation variation. The human genome contains a pseudogene similar to the 3' half of this gene. [provided by RefSeq, Oct 2008]

TYR links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 13 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-89284852-C-T is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.833

PP5

Variant 11-89284853-G-A is Pathogenic according to our data. Variant chr11-89284853-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 3782.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-89284853-G-A is described in Lovd as [Pathogenic]. Variant chr11-89284853-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TYR	NM_000372.5 link	c.1265G>A	p.Arg422Gln	missense_variant	Exon 4 of 5	ENST00000263321.6	NP_000363.1	P14679-1L8B082
TYR	XM_011542970.3 link	c.1265G>A	p.Arg422Gln	missense_variant	Exon 4 of 6		XP_011541272.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TYR	ENST00000263321.6 link	c.1265G>A	p.Arg422Gln	missense_variant	Exon 4 of 5	1	NM_000372.5	ENSP00000263321.4		P14679-1
TYR	ENST00000528243.1 link	n.263G>A		non_coding_transcript_exon_variant	Exon 2 of 3	5

Frequencies

GnomAD3 genomes

AF:

0.0000198

AC:

AN:

151780

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000194

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000599

AC:

AN:

250424

Hom.:

AF XY:

0.0000296

AC XY:

AN XY:

135348

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000291

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000218

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000885

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000384

AC:

AN:

1459988

Hom.:

Cov.:

AF XY:

0.0000413

AC XY:

AN XY:

726336

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000468

Gnomad4 OTH exome

AF:

0.0000332

GnomAD4 genome

AF:

0.0000198

AC:

AN:

151898

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74246

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000195

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000156

Hom.:

ExAC

AF:

0.0000494

AC:

EpiCase

AF:

0.0000546

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2Other:1

Retina International

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Sep 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 422 of the TYR protein (p.Arg422Gln). This variant is present in population databases (rs61754393, gnomAD 0.02%). This missense change has been observed in individual(s) with ocular albinism (PMID: 1900309, 31077556). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 3782). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt TYR protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects TYR function (PMID: 1900309). For these reasons, this variant has been classified as Pathogenic. -

Dec 20, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect with decreased tyrosine hydroxylase, dopa oxidase, DHI oxidase, copper-binding and/or catalytic activities (PMID: 1900309, 9242509, 1429711); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 1900309, 32552135, 10987646, 1900307, 1429711, 11284711, 9242509, 24392141, 27775880, 1943686, 18326704, 29437493, 31077556, 15146472, 2567165, 38145795, 36729443, 37605172, 34838614, 38542347) -

Oculocutaneous albinism type 1B

Pathogenic:1

Department of Medical Genetics, College of Basic Medicine, Army Medical University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Temperature-sensitive oculocutaneous albinism type 1

Pathogenic:1

Jul 01, 1991

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

TYR-related disorder

Pathogenic:1

Aug 02, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The TYR c.1265G>A variant is predicted to result in the amino acid substitution p.Arg422Gln. This variant has been reported in the compound heterozygous states in multiple individuals with oculocutaneous albinism (see for examples: Giebel et al. 1991. PubMed ID: 1900309; Zhong et al. 2019. PubMed ID: 31077556; Chuan et al. 2021. PubMed ID: 32552135). An alternate substitution of this amino acid (p.Arg422Trp) has also been reported in individuals with oculocutaneous albinism (King et al 2003. PubMed ID: 13680365). Functional studies have shown that the p.Arg422Gln substitution affects protein function (Toyofuku et al. 2001. PubMed ID: 11284711; Dolinska. 2014. PubMed ID: 24392141). This variant is reported in 0.022% of alleles in individuals of East Asian descent in gnomAD. This variant has been classified as pathogenic by multiple independent submitters to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/3782/). Given the evidence, we interpret this variant as pathogenic. -

SKIN/HAIR/EYE PIGMENTATION 3, LIGHT/DARK SKIN

Pathogenic:1

Feb 21, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oculocutaneous albinism type 1B;C4551504:Oculocutaneous albinism type 1A

Pathogenic:1

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_Supporting+PM3_VeryStrong+PP4+PP3 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.48

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.50

Eigen

Uncertain

0.63

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Uncertain

0.90

LIST_S2

Pathogenic

0.98

M_CAP

Pathogenic

0.52

MetaRNN

Pathogenic

0.83

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.0

PrimateAI

Benign

0.47

PROVEAN

Benign

-1.7

REVEL

Pathogenic

0.69

Sift

Uncertain

0.010

Sift4G

Benign

0.20

Polyphen

1.0

Vest4

0.88

MVP

1.0

MPC

0.042

ClinPred

0.55

GERP RS

4.7

Varity_R

0.21

gMVP

0.86

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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