rs876657698
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_001354604.2(MITF):c.1043G>A(p.Trp348*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 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 stop_gained
NM_001354604.2 stop_gained
Scores
5
1
1
Clinical Significance
Conservation
PhyloP100: 10.0
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 3-69959284-G-A is Pathogenic according to our data. Variant chr3-69959284-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 228362.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MITF | NM_001354604.2 | c.1043G>A | p.Trp348* | stop_gained | 9/10 | ENST00000352241.9 | NP_001341533.1 | |
MITF | NM_000248.4 | c.722G>A | p.Trp241* | stop_gained | 8/9 | ENST00000394351.9 | NP_000239.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MITF | ENST00000352241.9 | c.1043G>A | p.Trp348* | stop_gained | 9/10 | 1 | NM_001354604.2 | ENSP00000295600.8 | ||
MITF | ENST00000394351.9 | c.722G>A | p.Trp241* | stop_gained | 8/9 | 1 | NM_000248.4 | ENSP00000377880.3 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
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 | Jun 21, 2016 | The p.Trp342X variant in MITF has been reported by our laboratory in one individ ual with hearing loss and features of Waardenburg syndrome and segregated in two affected relatives. It has not been identified in large population studies. Th is nonsense variant leads to a premature termination codon at position 342, whic h is predicted to lead to a truncated or absent protein. Heterozygous loss-of-fu nction variants in the MITF gene are well described in individuals with Waardenb urg syndrome. In summary, this variant meets our criteria to be classified as p athogenic based on segregation with disease, consistent clinical features, extre mely low frequency in the general population, and predicted impact on the protei n. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
Vest4
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at