rs140663277
Variant summary
Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBS1BS2
The NM_001354604.2(MITF):c.366C>T(p.His122His) variant causes a synonymous change. The variant allele was found at a frequency of 0.00314 in 1,613,980 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Consequence
NM_001354604.2 synonymous
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -18 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MITF | ENST00000352241.9 | c.366C>T | p.His122His | synonymous_variant | Exon 3 of 10 | 1 | NM_001354604.2 | ENSP00000295600.8 | ||
MITF | ENST00000394351.9 | c.45C>T | p.His15His | synonymous_variant | Exon 2 of 9 | 1 | NM_000248.4 | ENSP00000377880.3 |
Frequencies
GnomAD3 genomes AF: 0.00207 AC: 315AN: 152144Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00289 AC: 725AN: 250976Hom.: 2 AF XY: 0.00318 AC XY: 431AN XY: 135666
GnomAD4 exome AF: 0.00325 AC: 4748AN: 1461718Hom.: 18 Cov.: 31 AF XY: 0.00328 AC XY: 2385AN XY: 727162
GnomAD4 genome AF: 0.00207 AC: 315AN: 152262Hom.: 0 Cov.: 32 AF XY: 0.00188 AC XY: 140AN XY: 74440
ClinVar
Submissions by phenotype
not provided Benign:6
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MITF: BP4, BS2 -
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not specified Benign:3
His122His in exon 3 of MITF: This variant is not expected to have clinical signi ficance because it does not alter an amino acid residue and is not located withi n the splice consensus sequence. It has been identified in 0.3% (30/8600) of Eur opean American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS; dbSNP rs140663277). -
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Hereditary cancer-predisposing syndrome Benign:2
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
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Waardenburg syndrome type 2A Benign:2
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This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Tietz syndrome;C1860339:Waardenburg syndrome type 2A;C3152204:Melanoma, cutaneous malignant, susceptibility to, 8 Benign:1
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Tietz syndrome Benign:1
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
MITF-related disorder Benign:1
This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
Melanoma, cutaneous malignant, susceptibility to, 8 Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at