rs1553703619
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_001354604.2(MITF):c.773_785dup(p.Asp263GlyfsTer5) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Consequence
MITF
NM_001354604.2 frameshift
NM_001354604.2 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 4.75
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 3-69949059-C-CTCGGGAAACTTGA is Pathogenic according to our data. Variant chr3-69949059-C-CTCGGGAAACTTGA is described in ClinVar as [Pathogenic]. Clinvar id is 505620.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MITF | NM_000248.4 | c.452_464dup | p.Asp156GlyfsTer5 | frameshift_variant | 5/9 | ENST00000394351.9 | |
MITF | NM_001354604.2 | c.773_785dup | p.Asp263GlyfsTer5 | frameshift_variant | 6/10 | ENST00000352241.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MITF | ENST00000352241.9 | c.773_785dup | p.Asp263GlyfsTer5 | frameshift_variant | 6/10 | 1 | NM_001354604.2 | P4 | |
MITF | ENST00000394351.9 | c.452_464dup | p.Asp156GlyfsTer5 | frameshift_variant | 5/9 | 1 | NM_000248.4 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 30
GnomAD4 exome
Cov.:
30
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Rare genetic deafness Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Feb 10, 2017 | The p.Asp263fs variant in MITF has not previously been reported in individuals w ith hearing loss or Waardenburg syndrome or in large population studies. This va riant is predicted to cause a frameshift, which alters the protein?s amino acid sequence beginning at position 263 and leads to a premature termination codon 5 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss-of-function of the MITF gene is an establi shed disease mechanism for Waardenburg syndrome. In summary, this variant meets criteria to be classified as pathogenic for Waardenburg syndrome in an autosomal dominant manner based on the predicted impact on the protein and extremely low allele frequency in the general population. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at