Variant chr11-89178603-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PM5PP5_Moderate

The NM_000372.5(TYR):c.650G>C(p.Arg217Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 152,076 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.0000066 ( 0 hom., cov: 32)

Consequence

TYR
NM_000372.5 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P: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 Likely_pathogenic. Variant got 6 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-C is Pathogenic according to our data. Variant chr11-89178603-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3574114.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TYR	NM_000372.5 link	c.650G>C	p.Arg217Pro	missense_variant	1/5	ENST00000263321.6	NP_000363.1	P14679-1L8B082
TYR	XM_011542970.3 link	c.650G>C	p.Arg217Pro	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>C	p.Arg217Pro	missense_variant	1/5	1	NM_000372.5	ENSP00000263321.4		P14679-1
TYR	ENST00000526139.1 link	n.711G>C		non_coding_transcript_exon_variant	1/3	1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152076

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152076

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74272

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

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

Jan 05, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.77

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Uncertain

0.040

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Pathogenic

0.86

Eigen

Benign

-0.10

Eigen_PC

Benign

-0.033

FATHMM_MKL

Uncertain

0.78

LIST_S2

Uncertain

0.97

M_CAP

Pathogenic

0.29

MetaRNN

Uncertain

0.64

MetaSVM

Uncertain

0.66

MutationAssessor

Uncertain

2.1

PrimateAI

Benign

0.32

PROVEAN

Benign

-1.7

REVEL

Pathogenic

0.69

Sift

Benign

0.20

Sift4G

Benign

0.24

Polyphen

0.51

Vest4

0.46

MutPred

0.68

Gain of catalytic residue at W218 (P = 0.0317);

MVP

0.96

MPC

0.020

ClinPred

0.46

GERP RS

3.7

Varity_R

0.84

gMVP

0.96

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