rs202246404
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Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2
The NM_001127453.2(GSDME):c.405-12T>C variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000389 in 1,608,426 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.00018 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00041 ( 4 hom. )
Consequence
GSDME
NM_001127453.2 splice_polypyrimidine_tract, intron
NM_001127453.2 splice_polypyrimidine_tract, intron
Scores
2
Splicing: ADA: 0.003600
2
Clinical Significance
Conservation
PhyloP100: 2.55
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 Benign. Variant got -20 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.82).
BP6
?
Variant 7-24719230-A-G is Benign according to our data. Variant chr7-24719230-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 163039.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
?
Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.000411 (598/1456088) while in subpopulation SAS AF= 0.0061 (526/86222). AF 95% confidence interval is 0.00567. There are 4 homozygotes in gnomad4_exome. There are 423 alleles in male gnomad4_exome subpopulation. Median coverage is 35. This position pass quality control queck.
BS2
?
High AC in GnomAd4 at 27 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GSDME | NM_001127453.2 | c.405-12T>C | splice_polypyrimidine_tract_variant, intron_variant | ENST00000645220.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GSDME | ENST00000645220.1 | c.405-12T>C | splice_polypyrimidine_tract_variant, intron_variant | NM_001127453.2 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000177 AC: 27AN: 152220Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000794 AC: 194AN: 244258Hom.: 1 AF XY: 0.00112 AC XY: 148AN XY: 132618
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GnomAD4 exome AF: 0.000411 AC: 598AN: 1456088Hom.: 4 Cov.: 35 AF XY: 0.000584 AC XY: 423AN XY: 724644
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GnomAD4 genome ? AF: 0.000177 AC: 27AN: 152338Hom.: 0 Cov.: 33 AF XY: 0.000242 AC XY: 18AN XY: 74496
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Nov 06, 2013 | 405-12T>C in Intron 3 of DFNA5: This variant is not expected to have clinical si gnificance because it does not diverge from the splice site consensus sequence a nd computational tools do not predict an impact to splicing. This variant has be en identified in 0.02% (1/4406) of African American chromosomes by the NHLBI Exo me Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs202246404). - |
Autosomal dominant nonsyndromic hearing loss 5 Benign:1
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | 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. - |
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 03, 2020 | - - |
Computational scores
Source:
Name
Calibrated prediction
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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dbscSNV1_ADA
Benign
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at