7-24719233-C-T

Position:

• chr7-24719233-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001127453.2(GSDME):​c.405-15G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.172 in 1,598,224 control chromosomes in the GnomAD database, including 27,573 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (2879 hom., cov: 32)
  • Exomes 𝑓: 0.17 (24694 hom.)
• Consequence: GSDME NM_001127453.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -2.37

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]

GSDME (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 7-24719233-C-T is Benign according to our data. Variant chr7-24719233-C-T is described in ClinVar as [Benign]. Clinvar id is 44842.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-24719233-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.446 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GSDME	NM_001127453.2	c.405-15G>A		intron_variant		ENST00000645220.1	NP_001120925.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GSDME	ENST00000645220.1	c.405-15G>A		intron_variant			NM_001127453.2	ENSP00000494186.1

Frequencies

GnomAD3 genomes AF: 0.181 AC: 27475 AN: 152008 Hom.: 2873 Cov.: 32

Gnomad AFR AF: 0.208

Gnomad AMI AF: 0.120

Gnomad AMR AF: 0.140

Gnomad ASJ AF: 0.123

Gnomad EAS AF: 0.462

Gnomad SAS AF: 0.326

Gnomad FIN AF: 0.166

Gnomad MID AF: 0.155

Gnomad NFE AF: 0.148

Gnomad OTH AF: 0.170

GnomAD3 exomes AF: 0.200 AC: 48731 AN: 243396 Hom.: 6067 AF XY: 0.205 AC XY: 27153 AN XY: 132204

Gnomad AFR exome AF: 0.208

Gnomad AMR exome AF: 0.154

Gnomad ASJ exome AF: 0.108

Gnomad EAS exome AF: 0.458

Gnomad SAS exome AF: 0.329

Gnomad FIN exome AF: 0.164

Gnomad NFE exome AF: 0.151

Gnomad OTH exome AF: 0.171

GnomAD4 exome AF: 0.171 AC: 246595 AN: 1446098 Hom.: 24694 Cov.: 35 AF XY: 0.175 AC XY: 125998 AN XY: 719976

Gnomad4 AFR exome AF: 0.206

Gnomad4 AMR exome AF: 0.150

Gnomad4 ASJ exome AF: 0.108

Gnomad4 EAS exome AF: 0.437

Gnomad4 SAS exome AF: 0.323

Gnomad4 FIN exome AF: 0.170

Gnomad4 NFE exome AF: 0.150

Gnomad4 OTH exome AF: 0.181

GnomAD4 genome AF: 0.181 AC: 27508 AN: 152126 Hom.: 2879 Cov.: 32 AF XY: 0.185 AC XY: 13762 AN XY: 74366

Gnomad4 AFR AF: 0.208

Gnomad4 AMR AF: 0.140

Gnomad4 ASJ AF: 0.123

Gnomad4 EAS AF: 0.462

Gnomad4 SAS AF: 0.326

Gnomad4 FIN AF: 0.166

Gnomad4 NFE AF: 0.148

Gnomad4 OTH AF: 0.178

Alfa AF: 0.119 Hom.: 359

Bravo AF: 0.179

Asia WGS AF: 0.380 AC: 1320 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal dominant nonsyndromic hearing loss 5 Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 24, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 07, 2012

405-15G>A in Intron 03 of DFNA5: This variant is not expected to have clinical s ignificance because it has been identified in 21.1% (788/3738) of African Americ an chromosomes from a broad population by the NHLBI Exome Sequencing Project (ht tp://evs.gs.washington.edu/EVS; dbSNP rs754553). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.081
DANN	Benign	0.31

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs754553; hg19: chr7-24758852; COSMIC: COSV61651769; COSMIC: COSV61651769;