rs1042602

chr11-89178528-C-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:3 B:7 O:3
• Conservation: PhyloP100: 4.50

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]

ACMG classification

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	UniProt
TYR	NM_000372.5	c.575C>A	p.Ser192Tyr	missense_variant	1/5	ENST00000263321.6
TYR	XM_011542970.3	c.575C>A	p.Ser192Tyr	missense_variant	1/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TYR	ENST00000263321.6	c.575C>A	p.Ser192Tyr	missense_variant	1/5	1	NM_000372.5	P1
TYR	ENST00000526139.1	n.636C>A		non_coding_transcript_exon_variant	1/3	1

Frequencies

GnomAD3 genomes AF: 0.242 AC: 36804 AN: 151964 Hom.: 6055 Cov.: 32

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

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.: 40 AF XY: 0.319 AC XY: 231839 AN XY: 727190

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.: 32 AF XY: 0.231 AC XY: 17181 AN XY: 74342

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:1 Uncertain:3 Benign:7 Other:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Tyrosinase-negative oculocutaneous albinism Uncertain:1 Benign:2 Other:1

Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
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. -

not specified Uncertain:1 Benign:2

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. -
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	- -

not provided Benign:2 Other:1

not provided, no classification provided	literature only	Retina International	-	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	TYR: BP4, BS1, BS2 -

Oculocutaneous albinism Uncertain:1 Benign: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

-

- -

SKIN/HAIR/EYE PIGMENTATION 3, LIGHT/DARK SKIN Other:1

association, no assertion criteria provided

literature only

OMIM

Oct 30, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Uncertain	0.0
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Pathogenic	0.88	D
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.74	T
MetaRNN	Benign	0.0054	T
MetaSVM	Benign	-1.8	T
MutationAssessor	Benign	1.8	L
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.35
Sift	Benign	0.031	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.38
MPC		0.069
ClinPred		0.015	T
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

Other links and lift over

dbSNP: rs1042602; hg19: chr11-88911696; COSMIC: COSV54472920;