rs757421220
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 4P and 9B. PVS1_StrongBP6BS1BS2
The NM_001127453.2(GSDME):c.1193_1196dupATAG(p.Ser399ArgfsTer2) variant causes a frameshift, stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000112 in 1,612,994 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_001127453.2 frameshift, stop_gained
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_benign. Variant got -5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
GSDME | NM_001127453.2 | c.1193_1196dupATAG | p.Ser399ArgfsTer2 | frameshift_variant, stop_gained | Exon 9 of 10 | ENST00000645220.1 | NP_001120925.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000394 AC: 6AN: 152174Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000756 AC: 19AN: 251428Hom.: 0 AF XY: 0.0000589 AC XY: 8AN XY: 135888
GnomAD4 exome AF: 0.000119 AC: 174AN: 1460702Hom.: 1 Cov.: 31 AF XY: 0.000121 AC XY: 88AN XY: 726670
GnomAD4 genome AF: 0.0000394 AC: 6AN: 152292Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74456
ClinVar
Submissions by phenotype
Autosomal dominant nonsyndromic hearing loss 5 Uncertain:2
- -
This variant results in a frameshift and is predicted to result in premature termination of the protein. It was observed by ICSL 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 for this variant, it could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene and cDNA change, and amino acid change. No publications were found based on this search. Due to the potential impact of frameshift variants and the lack of clarifying evidence, this variant is classified as a variant of unknown significance but suspicious for pathogenicity for this disease. -
not provided Benign:1
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is not a known mechanism of disease; Has not been previously published as pathogenic or benign to our knowledge -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at