rs61754362

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2PM5PP3_StrongPP5_Very_Strong

The NM_000372.5(TYR):c.613C>A(p.Pro205Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000898 in 1,614,020 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P205L) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000092 ( 0 hom. )

Consequence

TYR
NM_000372.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9O:1

Conservation

PhyloP100: 2.35

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 16 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-89178567-C-T is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.981

PP5

Variant 11-89178566-C-A is Pathogenic according to our data. Variant chr11-89178566-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 99572.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-89178566-C-A is described in Lovd as [Pathogenic]. Variant chr11-89178566-C-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.613C>A	p.Pro205Thr	missense_variant	Exon 1 of 5	ENST00000263321.6	NP_000363.1	P14679-1L8B082
TYR	XM_011542970.3 link	c.613C>A	p.Pro205Thr	missense_variant	Exon 1 of 6		XP_011541272.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TYR	ENST00000263321.6 link	c.613C>A	p.Pro205Thr	missense_variant	Exon 1 of 5	1	NM_000372.5	ENSP00000263321.4		P14679-1
TYR	ENST00000526139.1 link	n.674C>A		non_coding_transcript_exon_variant	Exon 1 of 3	1

Frequencies

GnomAD3 genomes

AF:

0.0000723

AC:

AN:

152144

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:

0.000162

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000199

AC:

AN:

251406

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135876

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000440

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000917

AC:

134

AN:

1461876

Hom.:

Cov.:

AF XY:

0.0000880

AC XY:

AN XY:

727238

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000112

Gnomad4 OTH exome

AF:

0.000132

GnomAD4 genome

AF:

0.0000723

AC:

AN:

152144

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

AN XY:

74318

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:

0.000162

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000133

Hom.:

Bravo

AF:

0.0000756

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.0000165

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2Other:1

Mar 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

TYR: PM3:Very Strong, PM2, PM5, PP4 -

Retina International

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Jan 07, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 205 of the TYR protein (p.Pro205Thr). This variant is present in population databases (rs61754362, gnomAD 0.006%). This missense change has been observed in individual(s) with clinical features of oculocutaneous albinism (PMID: 13680365; internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 99572). 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 expected to disrupt TYR protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -

Oculocutaneous albinism type 1A

Pathogenic:2

Aug 18, 2016

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 22, 2021

Genome-Nilou Lab

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oculocutaneous albinism type 1B;C2677190:SKIN/HAIR/EYE PIGMENTATION 3, LIGHT/DARK SKIN;C4551504:Oculocutaneous albinism type 1A

Pathogenic:1

Jan 29, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Albinism or congenital nystagmus

Pathogenic:1

Nov 11, 2024

NHS Central & South Genomic Laboratory Hub

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

TYR-related disorder

Pathogenic:1

Aug 29, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The TYR c.613C>A variant is predicted to result in the amino acid substitution p.Pro205Thr. This variant has been reported in multiple individuals with oculocutaneous albinism (Camand et al. 2001. PubMed ID: 11295837; King et al. 2003. PubMed ID: 13680365; Hutton and Spritz. 2008. PubMed ID: 18463683). This variant is reported in 0.0054% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Given the evidence, we interpret this variant as pathogenic. -

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

Pathogenic:1

Mar 15, 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

Sep 27, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.40

BayesDel_addAF

Pathogenic

0.42

BayesDel_noAF

Pathogenic

0.50

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.97

Eigen

Pathogenic

0.69

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Uncertain

0.90

LIST_S2

Pathogenic

0.98

M_CAP

Pathogenic

0.36

MetaRNN

Pathogenic

0.98

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

3.6

PrimateAI

Uncertain

0.52

PROVEAN

Pathogenic

-7.0

REVEL

Pathogenic

0.92

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0020

Polyphen

0.97

Vest4

0.89

MVP

1.0

MPC

0.065

ClinPred

0.98

GERP RS

5.2

Varity_R

0.80

gMVP

0.90

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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