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
Consequence
NM_001354604.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MITF | ENST00000352241.9 | c.1072G>A | p.Val358Met | missense_variant | Exon 9 of 10 | 1 | NM_001354604.2 | ENSP00000295600.8 | ||
MITF | ENST00000394351.9 | c.751G>A | p.Val251Met | missense_variant | Exon 8 of 9 | 1 | NM_000248.4 | ENSP00000377880.3 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461800Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 727204
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Waardenburg syndrome type 2A Uncertain:2
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MITF-related disorder Pathogenic:1
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
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
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
PM2_Supporting+PP3_Moderate -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at