chr3-69941238-G-A
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP6BS2
The NM_001354604.2(MITF):c.669G>A(p.Met223Ile) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000263 in 1,445,170 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_001354604.2 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MITF | NM_001354604.2 | c.669G>A | p.Met223Ile | missense_variant, splice_region_variant | Exon 5 of 10 | ENST00000352241.9 | NP_001341533.1 | |
MITF | NM_000248.4 | c.348G>A | p.Met116Ile | missense_variant, splice_region_variant | Exon 4 of 9 | ENST00000394351.9 | NP_000239.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MITF | ENST00000352241.9 | c.669G>A | p.Met223Ile | missense_variant, splice_region_variant | Exon 5 of 10 | 1 | NM_001354604.2 | ENSP00000295600.8 | ||
MITF | ENST00000394351.9 | c.348G>A | p.Met116Ile | missense_variant, splice_region_variant | Exon 4 of 9 | 1 | NM_000248.4 | ENSP00000377880.3 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 0.0000263 AC: 38AN: 1445170Hom.: 0 Cov.: 28 AF XY: 0.0000264 AC XY: 19AN XY: 720068
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Tietz syndrome;C1860339:Waardenburg syndrome type 2A;C3152204:Melanoma, cutaneous malignant, susceptibility to, 8 Uncertain:1
This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 116 of the MITF protein (p.Met116Ile). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MITF-related conditions. ClinVar contains an entry for this variant (Variation ID: 547529). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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
The MITF c.348G>A variant is predicted to result in the amino acid substitution p.Met116Ile. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as likely benign by one submitter in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/547529/). 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
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown; This variant is associated with the following publications: (PMID: 27640074) -
Waardenburg syndrome type 2A Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at