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

1
8
9

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:4B:8O: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]

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 rank MANE Protein UniProt
TYRNM_000372.5 linkc.575C>A p.Ser192Tyr missense_variant Exon 1 of 5 ENST00000263321.6 NP_000363.1 P14679-1L8B082
TYRXM_011542970.3 linkc.575C>A p.Ser192Tyr missense_variant Exon 1 of 6 XP_011541272.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TYRENST00000263321.6 linkc.575C>A p.Ser192Tyr missense_variant Exon 1 of 5 1 NM_000372.5 ENSP00000263321.4 P14679-1
TYRENST00000526139.1 linkn.636C>A non_coding_transcript_exon_variant Exon 1 of 3 1

Frequencies

GnomAD3 genomes
AF:
0.242
AC:
36804
AN:
151964
Hom.:
6055
Cov.:
32
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.:
40
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.:
32
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:2Uncertain:4Benign:8Other:3
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Oculocutaneous albinism type 1A Uncertain:1Benign:3Other:1
Jul 22, 2021
Genome-Nilou Lab
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
GeneReviews
Significance: not provided
Review Status: no classification provided
Collection Method: literature only

- -

Nov 07, 2019
Centre for Mendelian Genomics, University Medical Centre Ljubljana
Significance: Uncertain significance
Review Status: flagged submission
Collection Method: clinical testing

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. -

May 28, 2019
Mendelics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Medical Molecular Genetics Department, National Research Center
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not specified Uncertain:1Benign:2
Dec 16, 2014
Eurofins Ntd Llc (ga)
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Apr 07, 2023
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

-
PreventionGenetics, part of Exact Sciences
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

not provided Benign:2Other:1
Feb 01, 2025
CeGaT Center for Human Genetics Tuebingen
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

TYR: BP4, BS1, BS2 -

-
Retina International
Significance: not provided
Review Status: no classification provided
Collection Method: literature only

- -

Feb 03, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

SKIN/HAIR/EYE PIGMENTATION 3, LIGHT/DARK SKIN Pathogenic:1Other:1
Oct 30, 2017
OMIM
Significance: association
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Feb 29, 2024
Baylor Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Oculocutaneous albinism Uncertain:1Benign:1
Jan 12, 2018
Illumina Laboratory Services, Illumina
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

-
Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: research

- -

Oculocutaneous albinism type 1B Pathogenic:1
-
Institute of Human Genetics, University Hospital of Duesseldorf
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: not provided

- -

Albinism or congenital nystagmus Uncertain:1
Jul 01, 2024
NHS Central & South Genomic Laboratory Hub
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

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
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

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