chr11-89178603-G-A

Position:

chr11-89178603-G-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 12P and 1B. PM2PM5PP5_Very_StrongBP4

The NM_000372.5(TYR):c.650G>A(p.Arg217Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000222 in 1,612,568 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R217G) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.00041 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00020 ( 1 hom. )

Consequence

TYR
NM_000372.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11O:1

Conservation

PhyloP100: 1.29

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:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.

PP5

Variant 11-89178603-G-A is Pathogenic according to our data. Variant chr11-89178603-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 99575.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-89178603-G-A is described in Lovd as [Pathogenic]. Variant chr11-89178603-G-A is described in Lovd as [Likely_pathogenic]. Variant chr11-89178603-G-A is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.3665866). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TYR	NM_000372.5 link	c.650G>A	p.Arg217Gln	missense_variant	1/5	ENST00000263321.6	NP_000363.1	P14679-1L8B082
TYR	XM_011542970.3 link	c.650G>A	p.Arg217Gln	missense_variant	1/6		XP_011541272.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TYR	ENST00000263321.6 link	c.650G>A	p.Arg217Gln	missense_variant	1/5	1	NM_000372.5	ENSP00000263321.4		P14679-1
TYR	ENST00000526139.1 link	n.711G>A		non_coding_transcript_exon_variant	1/3	1

Frequencies

GnomAD3 genomes

AF:

0.000414

AC:

AN:

152076

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000266

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.000472

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000632

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000263

AC:

AN:

250834

Hom.:

AF XY:

0.000251

AC XY:

AN XY:

135596

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000871

Gnomad ASJ exome

AF:

0.000499

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000654

Gnomad FIN exome

AF:

0.000649

Gnomad NFE exome

AF:

0.000326

Gnomad OTH exome

AF:

0.000819

GnomAD4 exome

AF:

0.000202

AC:

295

AN:

1460492

Hom.:

Cov.:

AF XY:

0.000211

AC XY:

153

AN XY:

726444

show subpopulations

Gnomad4 AFR exome

AF:

0.000120

Gnomad4 AMR exome

AF:

0.000135

Gnomad4 ASJ exome

AF:

0.000537

Gnomad4 EAS exome

AF:

0.000126

Gnomad4 SAS exome

AF:

0.0000580

Gnomad4 FIN exome

AF:

0.000730

Gnomad4 NFE exome

AF:

0.000184

Gnomad4 OTH exome

AF:

0.000282

GnomAD4 genome

AF:

0.000414

AC:

AN:

152076

Hom.:

Cov.:

AF XY:

0.000404

AC XY:

AN XY:

74272

show subpopulations

Gnomad4 AFR

AF:

0.000266

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.000472

Gnomad4 NFE

AF:

0.000632

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000409

Hom.:

Bravo

AF:

0.000185

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000305

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.000237

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Tyrosinase-negative oculocutaneous albinism

Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Apr 16, 2024	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	May 15, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Sep 01, 2022	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.039%). Missense changes are a common disease-causing mechanism. Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000099575). The variant has been reported with a pathogenic variant as either compound heterozygous or homozygous in multiple similarly affected unrelated individuals (PMID: 18463683 , 27734839). A different missense change at the same codon (p.Arg217Trp) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000003795). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

not provided

Pathogenic:3Other:1

not provided, no classification provided	literature only	Retina International	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2024	TYR: PM3:Very Strong, PM1, PM2, PM5, PP4 -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 217 of the TYR protein (p.Arg217Gln). This variant is present in population databases (rs61754365, gnomAD 0.06%). This missense change has been observed in individual(s) with oculocutaneous albinism (PMID: 10987646, 28976636, 29345414). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 99575). 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 80%. This variant disrupts the p.Arg217 amino acid residue in TYR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1642278, 10987646, 27734839, 28266639). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 04, 2024	In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 34897530, 32966289, 8477259, 13680365, 19208379, 28976636, 28451379, 18463683, 31233279, 16170149, 19060277, 28629449, 31980526, 33050356, 34426522, 31589614, 34838614, 9259202) -

Oculocutaneous albinism

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	The TYR c.650G>A (p.Arg217Gln) missense variant has been reported in at least three studies and is found in a compound heterozygous state in at least five individuals with oculocutaneous albinism, with at least one individual carrying a pathogenic variant in trans (Wang et al. 2005; Hutton and Spritz 2008; GrÃ¸nskov et al. 2009). The variant was not found in 50 healthy unrelated control individuals (GrÃ¸nskov et al. 2009) and is reported at a frequency of 0.00048 in the European (non-Finnish) population of the Exome Aggregation Consortium. Two additional variants in the Arg217 residue (p.Arg217Trp and p.Arg217Gly) have been reported in individuals with oculocutaneous albinism in a compound heterozygous state (Hutton and Spritz 2008). Based on the evidence, the p.Arg217Gln variant is classified as likely pathogenic for oculocutaneous albinism. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 23, 2024	Variant summary: TYR c.650G>A (p.Arg217Gln) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00026 in 250834 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in TYR causing Oculocutaneous Albinism (0.00026 vs 0.0056), allowing no conclusion about variant significance. c.650G>A has been reported in the literature in multiple individuals affected with Oculocutaneous Albinism (King_2003, Oetting_2009). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 13680365, 19208379). ClinVar contains an entry for this variant (Variation ID: 99575). Based on the evidence outlined above, the variant was classified as pathogenic. -

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

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 12, 2024

- -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 26, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.072

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Uncertain

0.060

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Uncertain

0.58

Eigen

Benign

-0.58

Eigen_PC

Benign

-0.36

FATHMM_MKL

Benign

0.68

LIST_S2

Uncertain

0.92

M_CAP

Benign

0.067

MetaRNN

Benign

0.37

MetaSVM

Uncertain

-0.0091

MutationAssessor

Benign

-0.015

PrimateAI

Benign

0.29

PROVEAN

Benign

0.25

REVEL

Uncertain

0.55

Sift

Benign

0.45

Sift4G

Benign

0.37

Polyphen

0.0010

Vest4

0.67

MVP

0.88

MPC

0.011

ClinPred

1.0

GERP RS

3.7

Varity_R

0.058

gMVP

0.73

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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