11-89177964-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 1P and 2B. PP2BP4_Moderate

The NM_000372.5(TYR):c.11C>T(p.Ala4Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,613,982 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

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

Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

TYR
NM_000372.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.54

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

oculocutaneous albinism type 1
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
oculocutaneous albinism type 1A
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
Waardenburg syndrome type 2
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
minimal pigment oculocutaneous albinism type 1
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
oculocutaneous albinism type 1B
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
temperature-sensitive oculocutaneous albinism type 1
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

TYR links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -1 ACMG points.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 116 curated pathogenic missense variants (we use a threshold of 10). The gene has 3 curated benign missense variants. Gene score misZ: -1.9514 (below the threshold of 3.09). Trascript score misZ: -0.85521 (below the threshold of 3.09). GenCC associations: The gene is linked to Waardenburg syndrome type 2, oculocutaneous albinism type 1A, oculocutaneous albinism type 1, oculocutaneous albinism type 1B, minimal pigment oculocutaneous albinism type 1, temperature-sensitive oculocutaneous albinism type 1.

BP4

Computational evidence support a benign effect (MetaRNN=0.10681164).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TYR	NM_000372.5 link	c.11C>T	p.Ala4Val	missense_variant	Exon 1 of 5	ENST00000263321.6	NP_000363.1	P14679-1L8B082
TYR	XM_011542970.3 link	c.11C>T	p.Ala4Val	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.11C>T	p.Ala4Val	missense_variant	Exon 1 of 5	1	NM_000372.5	ENSP00000263321.4		P14679-1
TYR	ENST00000526139.1 link	n.72C>T		non_coding_transcript_exon_variant	Exon 1 of 3	1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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

GnomAD2 exomes

AF:

0.00

AC:

AN:

251440

AF XY:

0.00

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000130

AC:

AN:

1461780

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

727200

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86244

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53398

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5720

European-Non Finnish (NFE)

AF:

0.0000171

AC:

AN:

1111994

Other (OTH)

AF:

0.00

AC:

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.451

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152202

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74356

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41448

American (AMR)

AF:

0.00

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68042

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

May 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 4 of the TYR protein (p.Ala4Val). This variant is present in population databases (no rsID available, gnomAD 0.0008%). This variant has not been reported in the literature in individuals affected with TYR-related conditions. ClinVar contains an entry for this variant (Variation ID: 2107813). 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 not expected to disrupt TYR protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.090

BayesDel_addAF

Benign

-0.024

BayesDel_noAF

Benign

-0.27

CADD

Benign

(source)

DANN

Benign

0.81

DEOGEN2

Benign

0.26

Eigen

Benign

-0.68

Eigen_PC

Benign

-0.55

FATHMM_MKL

Benign

0.085

LIST_S2

Benign

0.68

M_CAP

Uncertain

0.096

MetaRNN

Benign

0.11

MetaSVM

Uncertain

0.47

MutationAssessor

Benign

0.42

PhyloP100

1.5

PrimateAI

Benign

0.35

PROVEAN

Benign

0.0

REVEL

Benign

0.24

Sift

Benign

0.58

Sift4G

Benign

0.68

Polyphen

0.0

Vest4

0.056

MutPred

0.43

Gain of sheet (P = 0.0016);

MVP

0.94

MPC

0.011

ClinPred

0.032

GERP RS

4.1

PromoterAI

-0.0094

Neutral

(source)

Varity_R

0.025

gMVP

0.55

Mutation Taster

=82/18

polymorphism

(source)

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

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11-89177964-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over