rs1271000541

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001354604.2(MITF):​c.1072G>A​(p.Val358Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,800 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

MITF
NM_001354604.2 missense

Scores

17
1
1

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:5

Conservation

PhyloP100: 10.0
Variant links:
Genes affected
MITF (HGNC:7105): (melanocyte inducing transcription factor) The protein encoded by this gene is a transcription factor that contains both basic helix-loop-helix and leucine zipper structural features. The encoded protein regulates melanocyte development and is responsible for pigment cell-specific transcription of the melanogenesis enzyme genes. Heterozygous mutations in the this gene cause auditory-pigmentary syndromes, such as Waardenburg syndrome type 2 and Tietz syndrome. [provided by RefSeq, Aug 2017]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.901

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MITFNM_001354604.2 linkc.1072G>A p.Val358Met missense_variant Exon 9 of 10 ENST00000352241.9 NP_001341533.1
MITFNM_000248.4 linkc.751G>A p.Val251Met missense_variant Exon 8 of 9 ENST00000394351.9 NP_000239.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MITFENST00000352241.9 linkc.1072G>A p.Val358Met missense_variant Exon 9 of 10 1 NM_001354604.2 ENSP00000295600.8 O75030-1
MITFENST00000394351.9 linkc.751G>A p.Val251Met missense_variant Exon 8 of 9 1 NM_000248.4 ENSP00000377880.3 O75030-9

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461800
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
727204
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:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:5
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Waardenburg syndrome type 2A Uncertain:2
Aug 07, 2018
Genomic Research Center, Shahid Beheshti University of Medical Sciences
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Nov 01, 2016
Center for Human Genetics, Inc, Center for Human Genetics, Inc
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

MITF-related disorder Pathogenic:1
Sep 26, 2024
PreventionGenetics, part of Exact Sciences
Significance: Likely pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

The MITF c.751G>A variant is predicted to result in the amino acid substitution p.Val251Met. This variant was reported in a patient with Waardenburg syndrome (Minami et al. 2019. PubMed ID: 30978479) and occurred de novo in a patient with bilateral sensorineural hearing loss (PreventionGenetics, internal data). Additionally, this variant was identified in an individual with congenital deafness and iris heterochromia (Table S2, Abolhassani et al. 2024. PubMed ID: 38374194). This variant has not been reported in a large population database, indicating it is rare. We interpret this variant as likely pathogenic. -

Tietz syndrome;C1860339:Waardenburg syndrome type 2A;C3152204:Melanoma, cutaneous malignant, susceptibility to, 8 Uncertain:1
Oct 03, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 251 of the MITF protein (p.Val251Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Waardenburg syndrome (PMID: 30978479). ClinVar contains an entry for this variant (Variation ID: 547535). 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 MITF protein function with a positive predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not specified Uncertain:1
Jun 07, 2019
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The p.Val251Met variant in MITF has been previously identified in one individual with hearing loss and heterochromia iridium by our laboratory and was absent from large population studies. This variant has been reported in ClinVar (Variation ID 547535). Computational prediction tools and conservation analysis suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Val251Met variant is uncertain. ACMG/AMP Criteria applied: PM2, PP3, PP4. -

Tietz syndrome;C1860339:Waardenburg syndrome type 2A;C3152204:Melanoma, cutaneous malignant, susceptibility to, 8;C4310625:Coloboma, osteopetrosis, microphthalmia, macrocephaly, albinism, and deafness Uncertain:1
-
Juno Genomics, Hangzhou Juno Genomics, Inc
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

PM2_Supporting+PP3_Moderate -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.58
D
BayesDel_noAF
Pathogenic
0.59
CADD
Pathogenic
33
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.98
.;D;.;.;.;.;D;.;.;.
Eigen
Pathogenic
0.96
Eigen_PC
Pathogenic
0.93
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
1.0
.;D;D;D;D;D;D;D;D;D
M_CAP
Pathogenic
0.35
D
MetaRNN
Pathogenic
0.90
D;D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
3.6
.;H;.;.;.;.;.;.;.;.
PrimateAI
Pathogenic
0.93
D
PROVEAN
Uncertain
-2.8
D;D;.;D;D;D;D;D;D;D
REVEL
Pathogenic
0.81
Sift
Pathogenic
0.0
D;D;.;D;D;D;D;D;D;D
Sift4G
Pathogenic
0.0010
D;D;.;D;D;D;D;D;D;D
Polyphen
1.0
D;.;D;.;D;D;.;D;D;.
Vest4
0.95
MutPred
0.74
Gain of disorder (P = 0.0182);.;Gain of disorder (P = 0.0182);.;.;.;.;.;.;.;
MVP
0.96
MPC
0.94
ClinPred
1.0
D
GERP RS
5.9
Varity_R
0.92
gMVP
0.90

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: rs1271000541; hg19: chr3-70008464; API