rs28940877

Positions:

chr11-89178218-T-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The ENST00000263321.6(TYR):c.265T>C(p.Cys89Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,614,078 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging 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. C89Y) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

TYR
ENST00000263321.6 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:6O:1

Conservation

PhyloP100: 7.58

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 18 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in ENST00000263321.6

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-89178219-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2137225.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.993

PP5

Variant 11-89178218-T-C is Pathogenic according to our data. Variant chr11-89178218-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 3781.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-89178218-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TYR	NM_000372.5 linkuse as main transcript	c.265T>C	p.Cys89Arg	missense_variant	1/5	ENST00000263321.6	NP_000363.1
TYR	XM_011542970.3 linkuse as main transcript	c.265T>C	p.Cys89Arg	missense_variant	1/6		XP_011541272.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TYR	ENST00000263321.6 linkuse as main transcript	c.265T>C	p.Cys89Arg	missense_variant	1/5	1	NM_000372.5	ENSP00000263321	P1	P14679-1
TYR	ENST00000526139.1 linkuse as main transcript	n.326T>C		non_coding_transcript_exon_variant	1/3	1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251148

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135738

show subpopulations

Gnomad AFR exome

AF:

0.0000616

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461862

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727230

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152216

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74362

show subpopulations

Gnomad4 AFR

AF:

0.0000482

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:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Tyrosinase-negative oculocutaneous albinism

Pathogenic:4

Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 03, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	May 16, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Nov 07, 2019	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PM2,PP3. -

not provided

Pathogenic:1Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 25, 2021	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Cys89 amino acid residue in TYR. Other variant(s) that disrupt this residue have been observed in individuals with TYR-related conditions (PMID: 25216246), which suggests that this may be a clinically significant amino acid residue. 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 TYR protein function. ClinVar contains an entry for this variant (Variation ID: 3781). This missense change has been observed in individual(s) with oculocutaneous albinism (PMID: 1899321, 16517127, 27734839). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (ExAC no frequency). This sequence change replaces cysteine with arginine at codon 89 of the TYR protein (p.Cys89Arg). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and arginine. -
not provided, no classification provided	literature only	Retina International	-	- -

Albinism;C0029131:Abnormal optic nerve morphology;C0035300:Abnormal retinal morphology;C0038379:Strabismus;C0078917:Ocular albinism;C0162835:Hypopigmentation of the skin;C0271385:Horizontal nystagmus;C1849221:Fair hair

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jan 01, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.32

BayesDel_noAF

Pathogenic

0.40

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.92

Eigen

Pathogenic

0.92

Eigen_PC

Pathogenic

0.88

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.99

M_CAP

Pathogenic

0.35

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

0.87

MutationAssessor

Pathogenic

3.6

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.82

PROVEAN

Pathogenic

-11

REVEL

Pathogenic

0.92

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.98

MutPred

0.97

Loss of helix (P = 0.0237);

MVP

0.97

MPC

0.073

ClinPred

0.97

GERP RS

6.1

Varity_R

0.94

gMVP

0.99

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