rs17149912

chr7-24702817-T-Cchr7-24702817-T-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001127453.2(GSDME):c.1200A>G(p.Ala400=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.166 in 1,612,490 control chromosomes in the GnomAD database, including 24,394 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2310 hom., cov: 33)
  • Exomes 𝑓: 0.17 (22084 hom.)
• Consequence: GSDME NM_001127453.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.285

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 7-24702817-T-C is Benign according to our data. Variant chr7-24702817-T-C is described in ClinVar as [Benign]. Clinvar id is 44840.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.285 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.255 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GSDME	NM_001127453.2	c.1200A>G	p.Ala400=	synonymous_variant	9/10	ENST00000645220.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GSDME	ENST00000645220.1	c.1200A>G	p.Ala400=	synonymous_variant	9/10		NM_001127453.2	P1

Frequencies

GnomAD3 genomes AF: 0.168 AC: 25534 AN: 152104 Hom.: 2312 Cov.: 33

Gnomad AFR AF: 0.126

Gnomad AMI AF: 0.0593

Gnomad AMR AF: 0.254

Gnomad ASJ AF: 0.185

Gnomad EAS AF: 0.267

Gnomad SAS AF: 0.231

Gnomad FIN AF: 0.212

Gnomad MID AF: 0.241

Gnomad NFE AF: 0.155

Gnomad OTH AF: 0.174

GnomAD3 exomes AF: 0.201 AC: 50594 AN: 251402 Hom.: 5793 AF XY: 0.197 AC XY: 26822 AN XY: 135878

Gnomad AFR exome AF: 0.129

Gnomad AMR exome AF: 0.324

Gnomad ASJ exome AF: 0.188

Gnomad EAS exome AF: 0.278

Gnomad SAS exome AF: 0.227

Gnomad FIN exome AF: 0.205

Gnomad NFE exome AF: 0.155

Gnomad OTH exome AF: 0.201

GnomAD4 exome AF: 0.166 AC: 242933 AN: 1460268 Hom.: 22084 Cov.: 31 AF XY: 0.169 AC XY: 122671 AN XY: 726456

Gnomad4 AFR exome AF: 0.128

Gnomad4 AMR exome AF: 0.314

Gnomad4 ASJ exome AF: 0.184

Gnomad4 EAS exome AF: 0.289

Gnomad4 SAS exome AF: 0.230

Gnomad4 FIN exome AF: 0.206

Gnomad4 NFE exome AF: 0.149

Gnomad4 OTH exome AF: 0.175

GnomAD4 genome AF: 0.168 AC: 25539 AN: 152222 Hom.: 2310 Cov.: 33 AF XY: 0.176 AC XY: 13098 AN XY: 74416

Gnomad4 AFR AF: 0.126

Gnomad4 AMR AF: 0.254

Gnomad4 ASJ AF: 0.185

Gnomad4 EAS AF: 0.267

Gnomad4 SAS AF: 0.233

Gnomad4 FIN AF: 0.212

Gnomad4 NFE AF: 0.155

Gnomad4 OTH AF: 0.172

Alfa AF: 0.148 Hom.: 3075

Bravo AF: 0.169

Asia WGS AF: 0.253 AC: 878 AN: 3478

EpiCase AF: 0.160

EpiControl AF: 0.157

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	Ala400Ala in Exon 09 of DFNA5: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue, is not located withi n the splice consensus sequence, and has been identified in 15.6% (1098/7020) of European American chromosomes from a broad population by the NHLBI Exome Sequen cing Project (http://evs.gs.washington.edu/EVS; dbSNP rs17149912). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 09, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Autosomal dominant nonsyndromic hearing loss 5 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
Cadd	Benign	4.8
Dann	Benign	0.42

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs17149912; hg19: chr7-24742436; COSMIC: COSV61651248; COSMIC: COSV61651248;