rs61753178

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2PM5PP3_StrongPP5_Very_Strong

The NM_000372.5(TYR):​c.61C>T​(p.Pro21Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000229 in 1,614,054 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. P21L) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000024 ( 0 hom. )

Consequence

TYR
NM_000372.5 missense

Scores

14
4
1

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:8O:1

Conservation

PhyloP100: 7.45
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 Pathogenic. Variant got 16 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr11-89178015-C-T is described in Lovd as [Pathogenic].
PP3
MetaRNN computational evidence supports a deleterious effect, 0.99
PP5
Variant 11-89178014-C-T is Pathogenic according to our data. Variant chr11-89178014-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 3793.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-89178014-C-T is described in Lovd as [Pathogenic]. Variant chr11-89178014-C-T is described in Lovd as [Likely_pathogenic]. Variant chr11-89178014-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TYRNM_000372.5 linkc.61C>T p.Pro21Ser missense_variant Exon 1 of 5 ENST00000263321.6 NP_000363.1 P14679-1L8B082
TYRXM_011542970.3 linkc.61C>T p.Pro21Ser 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.61C>T p.Pro21Ser missense_variant Exon 1 of 5 1 NM_000372.5 ENSP00000263321.4 P14679-1
TYRENST00000526139.1 linkn.122C>T non_coding_transcript_exon_variant Exon 1 of 3 1

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152172
Hom.:
0
Cov.:
32
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:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000358
AC:
9
AN:
251474
Hom.:
0
AF XY:
0.0000515
AC XY:
7
AN XY:
135904
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000791
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000239
AC:
35
AN:
1461882
Hom.:
0
Cov.:
31
AF XY:
0.0000248
AC XY:
18
AN XY:
727240
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000315
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152172
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74328
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:
0.0000294
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000277
Hom.:
0
Bravo
AF:
0.0000151
ExAC
AF:
0.0000494
AC:
6

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:8Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

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

- -

Sep 01, 2022
3billion, Medical Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.004%). Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.94; 3Cnet: 0.53). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000003793). The variant has been reported with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 1642278). A different missense change at the same codon (p.Pro21Leu) has been reported to be associated with TYR -related disorder (PMID: 22734612). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Jul 15, 1992
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

not provided Pathogenic:2Other:1
Feb 01, 2021
CeGaT Center for Human Genetics Tuebingen
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

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

- -

Feb 02, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 21 of the TYR protein (p.Pro21Ser). This variant is present in population databases (rs61753178, gnomAD 0.008%). This missense change has been observed in individuals with ocular albinism (PMID: 1642278, 13680365, 19060277, 20861488). ClinVar contains an entry for this variant (Variation ID: 3793). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt TYR protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -

Oculocutaneous albinism type 1B Pathogenic:1
Feb 19, 2024
Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence variant is a single nucleotide substitution (C>T) at position 61 of the coding sequence of the TYR gene that results in a proline to serine amino acid change at residue 21 of the tyrosinase protein. This is a previously reported variant (ClinVar 3793) that has been observed in numerous homozygous and compound heterozygous individuals affected by oculocutaneous albinism (PMID: 1642278, 13680365, 19060277, 26167114, 27734839, 30472657). This variant is present in 11 of 403646 alleles (0.0027%) in the gnomAD population dataset. Multiple bioinformatic tools predict that this amino acid change would be damaging, and the Pro21 residue at this position is highly conserved across the vertebrate species examined. Studies examining the functional consequence of this variant have not been published, to our knowledge. Based upon the evidence, we consider this variant to be pathogenic. ACMG Criteria: PM2, PM3, PP2, PP3, PS4 -

Oculocutaneous albinism type 1B;C2677190:SKIN/HAIR/EYE PIGMENTATION 3, LIGHT/DARK SKIN;C4551504:Oculocutaneous albinism type 1A Pathogenic:1
Apr 03, 2024
Fulgent Genetics, Fulgent Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

SKIN/HAIR/EYE PIGMENTATION 3, LIGHT/DARK SKIN Pathogenic:1
Mar 17, 2024
Baylor Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.77
BayesDel_addAF
Pathogenic
0.41
D
BayesDel_noAF
Pathogenic
0.55
CADD
Uncertain
25
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.89
D
Eigen
Pathogenic
0.95
Eigen_PC
Pathogenic
0.90
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Uncertain
0.92
D
M_CAP
Pathogenic
0.53
D
MetaRNN
Pathogenic
0.99
D
MetaSVM
Pathogenic
0.95
D
MutationAssessor
Pathogenic
3.6
H
PrimateAI
Uncertain
0.53
T
PROVEAN
Pathogenic
-6.3
D
REVEL
Pathogenic
0.94
Sift
Uncertain
0.0010
D
Sift4G
Uncertain
0.0090
D
Polyphen
1.0
D
Vest4
0.97
MutPred
0.91
Gain of disorder (P = 0.1295);
MVP
0.99
MPC
0.075
ClinPred
1.0
D
GERP RS
6.1
Varity_R
0.71
gMVP
0.95

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: rs61753178; hg19: chr11-88911182; COSMIC: COSV54474087; API