11-89227823-G-T

Variant summary

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

The NM_000372.5(TYR):​c.1037G>T​(p.Gly346Val) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,612,090 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/23 in silico tools predict a damaging outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G346E) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

TYR
NM_000372.5 missense, splice_region

Scores

15
3
1
Splicing: ADA: 0.9998
2

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 9.36
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 chr11-89227823-G-A is described in Lovd as [Pathogenic].
PP3
MetaRNN computational evidence supports a deleterious effect, 0.958
PP5
Variant 11-89227823-G-T is Pathogenic according to our data. Variant chr11-89227823-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 437986.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-89227823-G-T is described in Lovd as [Pathogenic]. Variant chr11-89227823-G-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TYRNM_000372.5 linkc.1037G>T p.Gly346Val missense_variant, splice_region_variant Exon 3 of 5 ENST00000263321.6 NP_000363.1 P14679-1L8B082
TYRXM_011542970.3 linkc.1037G>T p.Gly346Val missense_variant, splice_region_variant Exon 3 of 6 XP_011541272.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TYRENST00000263321.6 linkc.1037G>T p.Gly346Val missense_variant, splice_region_variant Exon 3 of 5 1 NM_000372.5 ENSP00000263321.4 P14679-1

Frequencies

GnomAD3 genomes
AF:
0.00000658
AC:
1
AN:
151904
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:
0.000208
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000800
AC:
2
AN:
250116
Hom.:
0
AF XY:
0.0000148
AC XY:
2
AN XY:
135232
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:
0.0000654
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000205
AC:
3
AN:
1460186
Hom.:
0
Cov.:
32
AF XY:
0.00000413
AC XY:
3
AN XY:
726482
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:
0.0000348
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000658
AC:
1
AN:
151904
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74182
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:
0.000208
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Oculocutaneous albinism type 1A Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingIntergen, Intergen Genetics and Rare Diseases Diagnosis CenterSep 05, 2023- -
Abnormality of the eye Pathogenic:1
Likely pathogenic, no assertion criteria providedresearchNIHR Bioresource Rare Diseases, University of CambridgeJan 01, 2015Rare ocular disorder associated to additional undetermined phenotypes -
not provided Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpNov 04, 2024This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 346 of the TYR protein (p.Gly346Val). This variant is present in population databases (rs773970123, gnomAD 0.007%). This missense change has been observed in individual(s) with ocular albinism (PMID: 16098056, 33800529). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 437986). 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%. This variant disrupts the p.Gly346 amino acid residue in TYR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8026428, 25216246, 28266639, 31077556). 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. -
SKIN/HAIR/EYE PIGMENTATION 3, LIGHT/DARK SKIN Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsJan 27, 2023- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.98
BayesDel_addAF
Pathogenic
0.41
D
BayesDel_noAF
Pathogenic
0.53
CADD
Pathogenic
32
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.97
D
Eigen
Pathogenic
0.87
Eigen_PC
Pathogenic
0.81
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Pathogenic
0.98
D
M_CAP
Pathogenic
0.37
D
MetaRNN
Pathogenic
0.96
D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
3.7
H
PrimateAI
Uncertain
0.68
T
PROVEAN
Pathogenic
-6.7
D
REVEL
Pathogenic
0.97
Sift
Uncertain
0.010
D
Sift4G
Pathogenic
0.0010
D
Polyphen
0.98
D
Vest4
0.99
MutPred
0.77
Loss of loop (P = 0.0512);
MVP
1.0
MPC
0.074
ClinPred
0.99
D
GERP RS
5.1
Varity_R
0.95
gMVP
0.94

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.99
SpliceAI score (max)
0.14
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: rs773970123; hg19: chr11-88960991; COSMIC: COSV54477338; API