rs757421220
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Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 4P and 5B. PVS1_StrongBP6BS2
The NM_001127453.2(GSDME):c.1196_1197insATAG(p.Ser399ArgfsTer2) variant causes a stop gained, frameshift 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
Genomes: 𝑓 0.000039 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00012 ( 1 hom. )
Consequence
GSDME
NM_001127453.2 stop_gained, frameshift
NM_001127453.2 stop_gained, frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.812
Genes affected
GSDME (HGNC:2810): (gasdermin E) Hearing impairment is a heterogeneous condition with over 40 loci described. The protein encoded by this gene is expressed in fetal cochlea, however, its function is not known. Nonsyndromic hearing impairment is associated with a mutation in this gene. Three transcript variants encoding two different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -1 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.198 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
BP6
Variant 7-24702820-G-GCTAT is Benign according to our data. Variant chr7-24702820-G-GCTAT is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 225338.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.
BS2
High AC in GnomAd4 at 6 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
GSDME | NM_001127453.2 | c.1196_1197insATAG | p.Ser399ArgfsTer2 | stop_gained, frameshift_variant | 9/10 | ENST00000645220.1 | NP_001120925.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
GSDME | ENST00000645220.1 | c.1196_1197insATAG | p.Ser399ArgfsTer2 | stop_gained, frameshift_variant | 9/10 | NM_001127453.2 | ENSP00000494186 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000394 AC: 6AN: 152174Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000756 AC: 19AN: 251428Hom.: 0 AF XY: 0.0000589 AC XY: 8AN XY: 135888
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GnomAD4 exome AF: 0.000119 AC: 174AN: 1460702Hom.: 1 Cov.: 31 AF XY: 0.000121 AC XY: 88AN XY: 726670
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GnomAD4 genome AF: 0.0000394 AC: 6AN: 152292Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74456
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Autosomal dominant nonsyndromic hearing loss 5 Uncertain:2
Uncertain significance, criteria provided, single submitter | reference population | Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center | Mar 18, 2016 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Dec 15, 2018 | 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
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Sep 15, 2020 | 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
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at