rs1195515853
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP3_ModerateBS2
The NM_001354604.2(MITF):c.1040G>A(p.Arg347His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000212 in 1,461,766 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R347C) has been classified as Uncertain significance.
Frequency
Consequence
NM_001354604.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MITF | NM_001354604.2 | c.1040G>A | p.Arg347His | missense_variant | 9/10 | ENST00000352241.9 | |
MITF | NM_000248.4 | c.719G>A | p.Arg240His | missense_variant | 8/9 | ENST00000394351.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MITF | ENST00000352241.9 | c.1040G>A | p.Arg347His | missense_variant | 9/10 | 1 | NM_001354604.2 | P4 | |
MITF | ENST00000394351.9 | c.719G>A | p.Arg240His | missense_variant | 8/9 | 1 | NM_000248.4 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.00000399 AC: 1AN: 250532Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135442
GnomAD4 exome AF: 0.0000212 AC: 31AN: 1461766Hom.: 0 Cov.: 32 AF XY: 0.0000124 AC XY: 9AN XY: 727182
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jul 10, 2019 | The p.Arg240His variant in MITF has been reported by our laboratory in 1 individual with hearing loss, and was also identified in a reportedly unaffected parent. This variant was identified in 0.0008% (1/113036) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). 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.Arg240His variant is uncertain. ACMG/AMP Criteria applied: PM2, PP3. - |
Tietz syndrome;C1860339:Waardenburg syndrome type 2A;C3152204:Melanoma, cutaneous malignant, susceptibility to, 8 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 240 of the MITF protein (p.Arg240His). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individual(s) with non-syndromic hearing loss (PMID: 32728090). ClinVar contains an entry for this variant (Variation ID: 505101). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MITF protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects MITF function (PMID: 32728090). 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. - |
MITF-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Dec 06, 2023 | The MITF c.719G>A variant is predicted to result in the amino acid substitution p.Arg240His. This variant was reported in the homozygous state in three siblings from a consanguineous family with nonsyndromic hearing loss without pigmentation abnormalities (described as p.Arg341His, Thongpradit et al. 2020. PubMed ID: 32728090). Five heterozygous carriers in this family were reported to be asymptomatic. Functional studies showed that this variant results in reduced transcriptional activity and altered subcellular localization (Thongpradit et al. 2020. PubMed ID: 32728090). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Different nucleotide substitutions affecting the same amino acid (p.Arg240Gly and p.Arg240Cys) have been reported in the heterozygous state in four individuals with nonsyndromic hearing loss from three families but was also present in two unaffected family members, and in the homozygous state in one individual with Waardenburg syndrome (Thongpradit et al. 2020. PubMed ID: 32728090; Somashekar et al. 2019. PubMed ID: 30394532; described as c.1021C>G, Li et al. 2021. PubMed ID: 33724713; Zhang et al. 2018. PubMed ID: 29484430). Although we suspect that the c.719G>A (p.Arg240His) variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Sep 07, 2023 | Observed in homozygous state in three siblings with nonsyndromic hearing loss in the literature; heterozygous parents were unaffected; reported as c.1022G>A p.(R341H) using alternate nomenclature (Thongpradit et al., 2020); Published functional studies suggest a reduction of TYR promoter activity compared to wildtype and mislocalization of the resulting protein, however, the effect on downstream target genes was not assessed (Thongpradit et al., 2020); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 32728090) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at