rs61753185

chr11-89178183-G-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_000372.5(TYR):c.230G>A(p.Arg77Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000595 in 1,614,144 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R77W) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000059 (0 hom.)
• Consequence: TYR NM_000372.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:18 O:1
• Conservation: PhyloP100: 9.48

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 Pathogenic. Variant got 16 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_000372.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-89178182-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 99553.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.919
• PP5: Variant 11-89178183-G-A is Pathogenic according to our data. Variant chr11-89178183-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 3776.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-89178183-G-A is described in Lovd as [Pathogenic]. Variant chr11-89178183-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TYR	NM_000372.5	c.230G>A	p.Arg77Gln	missense_variant	1/5	ENST00000263321.6
TYR	XM_011542970.3	c.230G>A	p.Arg77Gln	missense_variant	1/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TYR	ENST00000263321.6	c.230G>A	p.Arg77Gln	missense_variant	1/5	1	NM_000372.5	P1
TYR	ENST00000526139.1	n.291G>A		non_coding_transcript_exon_variant	1/3	1

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152198 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000837 AC: 21 AN: 251030 Hom.: 0 AF XY: 0.0000737 AC XY: 10 AN XY: 135656

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0000981

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000123

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000588 AC: 86 AN: 1461828 Hom.: 0 Cov.: 31 AF XY: 0.0000564 AC XY: 41 AN XY: 727202

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.0000765

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.000112

Gnomad4 NFE exome AF: 0.0000495

Gnomad4 OTH exome AF: 0.000132

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152316 Hom.: 0 Cov.: 32 AF XY: 0.0000671 AC XY: 5 AN XY: 74476

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000111 Hom.: 0

Bravo AF: 0.0000604

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.0000988 AC: 12

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:18 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Tyrosinase-negative oculocutaneous albinism Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jan 22, 2020	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 15, 1992	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 16, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Pathology and Clinical Laboratory Medicine, King Fahad Medical City	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota	Feb 09, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
Pathogenic, no assertion criteria provided	clinical testing	Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	Jan 29, 2019	- -

not provided Pathogenic:5 Other:1

not provided, no classification provided	literature only	Retina International	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 11, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 26, 2022	Published functional studies demonstrate a damaging effect: abnormal protein folding and no in vitro enzyme activity (Dolinksa et al., 2017); This variant is associated with the following publications: (PMID: 23324268, 2113511, 1642278, 32552793, 10929771, 32427313, 21985232, 34487524, 27775880, 31077556, 28976636) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 04, 2024	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 77 of the TYR protein (p.Arg77Gln). This variant is present in population databases (rs61753185, gnomAD 0.01%). This missense change has been observed in individuals with oculocutaneous albinism (PMID: 21985232, 31077556). ClinVar contains an entry for this variant (Variation ID: 3776). 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 expected to disrupt TYR protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects TYR function (PMID: 21985232). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 12, 2017	- -

SKIN/HAIR/EYE PIGMENTATION 3, LIGHT/DARK SKIN Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 07, 2023	- -
Pathogenic, criteria provided, single submitter	research	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 14, 2024	- -

Oculocutaneous albinism type 1B Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City

Jan 29, 2019

- -

Oculocutaneous albinism type 1B;C2677190:SKIN/HAIR/EYE PIGMENTATION 3, LIGHT/DARK SKIN;C4551504:Tyrosinase-negative oculocutaneous albinism Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 03, 2022

- -

See cases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Center for Personalized Medicine, Children's Hospital Los Angeles

Dec 21, 2022

- -

TYR-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 14, 2023

The TYR c.230G>A variant is predicted to result in the amino acid substitution p.Arg77Gln. This variant has been reported in the homozygous and compound heterozygous states in individuals with oculocutaneous albinism (see for examples Kikuchi et al. 1990. PubMed ID: 2113511; Kono et al. 2012. PubMed ID: 21985232; Marti et al. 2018. PubMed ID: 28976636). Functional studies support the pathogenicity of this variant (Dolinska et al. 2017. PubMed ID: 27775880; Kono et al. 2012. PubMed ID: 219852320). This variant is reported in 0.012% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-88911351-G-A). This variant has been classified as pathogenic by multiple independent submitters to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/3776/). Given all the evidence, we interpret c.230G>A (p.Arg77Gln) as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.65
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.40
Cadd	Pathogenic	31
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.85	D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Pathogenic	0.87	D
MutationAssessor	Pathogenic	3.6	H
MutationTaster	Benign	1.0	A
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-3.7	D
REVEL	Pathogenic	0.88
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.88
MVP		0.98
MPC		0.074
ClinPred		0.98	D
GERP RS		6.1
Varity_R		0.83
gMVP		0.96

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs61753185; hg19: chr11-88911351; COSMIC: COSV54473651;