rs1042602

Positions:

chr11-89178528-C-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_000372.5(TYR):c.575C>A(p.Ser192Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.314 in 1,613,856 control chromosomes in the GnomAD database, including 90,450 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.24 ( 6055 hom., cov: 32)

Exomes 𝑓: 0.32 ( 84395 hom. )

Consequence

TYR
NM_000372.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:4B:7O:3

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 Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0053822994).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.361 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TYR	NM_000372.5 linkuse as main transcript	c.575C>A	p.Ser192Tyr	missense_variant	1/5	ENST00000263321.6	NP_000363.1
TYR	XM_011542970.3 linkuse as main transcript	c.575C>A	p.Ser192Tyr	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.575C>A	p.Ser192Tyr	missense_variant	1/5	1	NM_000372.5	ENSP00000263321	P1	P14679-1
TYR	ENST00000526139.1 linkuse as main transcript	n.636C>A		non_coding_transcript_exon_variant	1/3	1

Frequencies

GnomAD3 genomes

AF:

0.242

AC:

36804

AN:

151964

Hom.:

6055

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0670

Gnomad AMI

AF:

0.343

Gnomad AMR

AF:

0.272

Gnomad ASJ

AF:

0.455

Gnomad EAS

AF:

0.00232

Gnomad SAS

AF:

0.0979

Gnomad FIN

AF:

0.183

Gnomad MID

AF:

0.408

Gnomad NFE

AF:

0.365

Gnomad OTH

AF:

0.304

GnomAD3 exomes

AF:

0.254

AC:

63923

AN:

251456

Hom.:

10823

AF XY:

0.261

AC XY:

35434

AN XY:

135900

show subpopulations

Gnomad AFR exome

AF:

0.0594

Gnomad AMR exome

AF:

0.207

Gnomad ASJ exome

AF:

0.450

Gnomad EAS exome

AF:

0.000815

Gnomad SAS exome

AF:

0.111

Gnomad FIN exome

AF:

0.182

Gnomad NFE exome

AF:

0.369

Gnomad OTH exome

AF:

0.319

GnomAD4 exome

AF:

0.322

AC:

470738

AN:

1461774

Hom.:

84395

Cov.:

AF XY:

0.319

AC XY:

231839

AN XY:

727190

show subpopulations

Gnomad4 AFR exome

AF:

0.0507

Gnomad4 AMR exome

AF:

0.216

Gnomad4 ASJ exome

AF:

0.449

Gnomad4 EAS exome

AF:

0.000932

Gnomad4 SAS exome

AF:

0.114

Gnomad4 FIN exome

AF:

0.181

Gnomad4 NFE exome

AF:

0.367

Gnomad4 OTH exome

AF:

0.300

GnomAD4 genome

AF:

0.242

AC:

36791

AN:

152082

Hom.:

6055

Cov.:

AF XY:

0.231

AC XY:

17181

AN XY:

74342

show subpopulations

Gnomad4 AFR

AF:

0.0668

Gnomad4 AMR

AF:

0.271

Gnomad4 ASJ

AF:

0.455

Gnomad4 EAS

AF:

0.00232

Gnomad4 SAS

AF:

0.0986

Gnomad4 FIN

AF:

0.183

Gnomad4 NFE

AF:

0.365

Gnomad4 OTH

AF:

0.301

Alfa

AF:

0.349

Hom.:

25555

Bravo

AF:

0.246

TwinsUK

AF:

0.376

AC:

1396

ALSPAC

AF:

0.375

AC:

1445

ESP6500AA

AF:

0.0756

AC:

333

ESP6500EA

AF:

0.377

AC:

3239

ExAC

AF:

0.252

AC:

30574

Asia WGS

AF:

0.0530

AC:

185

AN:

3478

EpiCase

AF:

0.391

EpiControl

AF:

0.401

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:4Benign:7Other:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Tyrosinase-negative oculocutaneous albinism

Uncertain:1Benign:3Other:1

Uncertain significance, flagged submission	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Nov 07, 2019	This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PS3,PP3,PP4,BP6,BS1,BA1. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Benign, criteria provided, single submitter	clinical testing	Medical Molecular Genetics Department, National Research Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not provided

Pathogenic:1Benign:1Other:1

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	TYR: PM3:Very Strong, PM2, PP4, BP4 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
not provided, no classification provided	literature only	Retina International	-	- -

not specified

Uncertain:1Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	This variant is very common in the general population, being documented in 45% of alleles in individuals of Ashkenazi Jewish descent (http://gnomad.broadinstitute.org/variant/11-88911696-C-A). Given the high allele frequency, including thousands of homozygotes this variant is not considered pathogenic individually. However, when this variant is in cis (present in the same copy of TYR) with the variant c.1205G>A (p.Arg402Gln), there is strong evidence that they create a pathogenic allele. Functional and phenotypic studies of the complex allele (p.[Arg402Gln;Ser192Tyr]; commonly referred to as a haplotype in the literature) indicate that the two substitutions have a compound effect on thermal stability of the protein and phenotypic spectrum of the individual (Tripathi et al. 1991. PubMed ID: 1820207; Chaki et al. 2011. PubMed ID: 20861851; Jagirdar et al. 2014. PubMed ID: 24739399). The p.[Arg402Gln;Ser192Tyr] allele is thought to be a recombination of the two individual variant alleles and is reported in ~1-2% of alleles (Jagirdar et al. 2014. PubMed ID: 24739399; Norman et al. 2017. PubMed ID: 28667292). However, this complex allele is enriched (up to 20%) in OCA patients with only one previously identified pathogenic variant in TYR (Lasseaux et al. 2018. PubMed ID: 29345414; Grønskov et al. 2019. PubMed ID: 30679655; Campbell et al. 2019. PubMed ID: 31719542). Given the evidence, we interpret the p.[Arg402Gln;Ser192Tyr] allele as likely pathogenic. When it is unclear whether the c.575C>A (p.Ser192Tyr) variant is part of the complex allele or not, then the clinical significance of it is uncertain. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 16, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 07, 2023	Variant summary: TYR c.575C>A (p.Ser192Tyr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.25 in 251456 control chromosomes in the gnomAD database, including 10823 homozygotes. The observed variant frequency is approximately 45-fold of the estimated maximal expected allele frequency for a pathogenic variant in TYR causing Oculocutaneous Albinism phenotype (0.0056), strongly suggesting that the variant is benign. c.575C>A has been reported in the literature in individuals affected with Oculocutaneous Albinism and nystagmus without strong evidence of causality (Wei_2015, Thomas_2017). These reports do not provide unequivocal conclusions about association of the variant with Oculocutaneous Albinism. At least two publications report experimental evidence evaluating an impact on protein function, showing ~60% of wildtype enzymatic activity and a reduction in pigment production in cells with the variant construct. Seven submitters have submitted clinical-significance assessments for this variant to ClinVar after 2014, and reported the variant with conflicting assessments (four as benign, one as VUS, one as pathogenic, and one as association). Based on the evidence outlined above, the variant was classified as likely benign. -

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

Pathogenic:1Other:1

association, no assertion criteria provided	literature only	OMIM	Oct 30, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 29, 2024	- -

Oculocutaneous albinism

Uncertain:1Benign:1

Uncertain significance, no assertion criteria provided	research	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	-	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Oculocutaneous albinism type 1B

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

not provided

Institute of Human Genetics, University Hospital of Duesseldorf

- -

Albinism or congenital nystagmus

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

NHS Central & South Genomic Laboratory Hub

Jul 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Uncertain

0.0

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.88

Eigen

Uncertain

0.49

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.74

MetaRNN

Benign

0.0054

MetaSVM

Benign

-1.8

MutationAssessor

Benign

1.8

MutationTaster

Benign

1.0

PrimateAI

Benign

0.44

PROVEAN

Uncertain

-2.8

REVEL

Uncertain

0.35

Sift

Benign

0.031

Sift4G

Uncertain

0.0030

Polyphen

1.0

Vest4

0.38

MPC

0.069

ClinPred

0.015

GERP RS

6.1

Varity_R

0.16

gMVP

0.69

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