11-89177955-T-C

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1PS1_ModeratePM2PP5_Very_Strong

The NM_000372.5(TYR):c.2T>C(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.00000124 in 1,613,914 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 (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

TYR
NM_000372.5 start_lost

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:2O:1

Conservation

PhyloP100: 4.50

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 20 ACMG points.

PVS1

Start lost variant, next in-frame start position is after 16 pathogenic variants. Next in-frame start position is after 90 CDS bases. Genomic position: 89178043. Lost 0.057 part of the original CDS.

PS1

Another start lost variant in NM_000372.5 (TYR) was described as [Pathogenic] in Lovd

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 11-89177955-T-C is Pathogenic according to our data. Variant chr11-89177955-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 99561.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-89177955-T-C is described in Lovd as [Pathogenic]. Variant chr11-89177955-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TYR	NM_000372.5 link	c.2T>C	p.Met1?	start_lost	Exon 1 of 5	ENST00000263321.6	NP_000363.1	P14679-1L8B082
TYR	XM_011542970.3 link	c.2T>C	p.Met1?	start_lost	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.2T>C	p.Met1?	start_lost	Exon 1 of 5	1	NM_000372.5	ENSP00000263321.4		P14679-1
TYR	ENST00000526139.1 link	n.63T>C		non_coding_transcript_exon_variant	Exon 1 of 3	1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152214

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461700

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727154

show subpopulations

Gnomad4 AFR exome

AF:

0.00

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:

0.00000657

AC:

AN:

152214

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74364

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2Other:1

Feb 21, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Initiation codon variant in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 10671066, 28378818, 30219046) -

Retina International

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Apr 06, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the TYR protein in which other variant(s) (p.Pro21Ser) have been determined to be pathogenic (PMID: 1642278, 13680365, 19060277, 20861488). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 99561). Disruption of the initiator codon has been observed in individual(s) with oculocutaneous albinism (PMID: 30472657). This variant is not present in population databases (gnomAD no frequency). This sequence change affects the initiator methionine of the TYR mRNA. The next in-frame methionine is located at codon 31. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.50

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.33

Eigen

Uncertain

0.49

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.90

M_CAP

Pathogenic

0.87

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

1.1

PROVEAN

Benign

-0.81

REVEL

Pathogenic

0.73

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0030

Polyphen

0.98

Vest4

0.92

MutPred

0.89

Gain of relative solvent accessibility (P = 0.0023);

MVP

1.0

ClinPred

0.99

GERP RS

6.1

Varity_R

0.74

gMVP

0.80

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