NM_001127453.2:c.447A>G

Variant names:

• chr7-24719176-T-C
• rs876305
• NM_001127453.2:c.447A>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.447A>G​(p.Glu149Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.485 in 1,611,166 control chromosomes in the GnomAD database, including 206,645 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.57 (27315 hom., cov: 33)
  • Exomes 𝑓: 0.48 (179330 hom.)
• Consequence: GSDME NM_001127453.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.873

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=-0.74).
• BP6: Variant 7-24719176-T-C is Benign according to our data. Variant chr7-24719176-T-C is described in ClinVar as [Benign]. Clinvar id is 44844.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-24719176-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.873 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.967 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GSDME	NM_001127453.2	c.447A>G	p.Glu149Glu	synonymous_variant	Exon 4 of 10	ENST00000645220.1	NP_001120925.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GSDME	ENST00000645220.1	c.447A>G	p.Glu149Glu	synonymous_variant	Exon 4 of 10		NM_001127453.2	ENSP00000494186.1

Frequencies

GnomAD3 genomes AF: 0.571 AC: 86843 AN: 152014 Hom.: 27250 Cov.: 33

Gnomad AFR AF: 0.781

Gnomad AMI AF: 0.260

Gnomad AMR AF: 0.619

Gnomad ASJ AF: 0.384

Gnomad EAS AF: 0.989

Gnomad SAS AF: 0.722

Gnomad FIN AF: 0.455

Gnomad MID AF: 0.510

Gnomad NFE AF: 0.424

Gnomad OTH AF: 0.531

GnomAD3 exomes AF: 0.570 AC: 142708 AN: 250270 Hom.: 45425 AF XY: 0.559 AC XY: 75679 AN XY: 135362

Gnomad AFR exome AF: 0.788

Gnomad AMR exome AF: 0.739

Gnomad ASJ exome AF: 0.382

Gnomad EAS exome AF: 0.992

Gnomad SAS exome AF: 0.709

Gnomad FIN exome AF: 0.453

Gnomad NFE exome AF: 0.423

Gnomad OTH exome AF: 0.513

GnomAD4 exome AF: 0.476 AC: 694100 AN: 1459034 Hom.: 179330 Cov.: 52 AF XY: 0.480 AC XY: 348534 AN XY: 725948

Gnomad4 AFR exome AF: 0.795

Gnomad4 AMR exome AF: 0.722

Gnomad4 ASJ exome AF: 0.379

Gnomad4 EAS exome AF: 0.996

Gnomad4 SAS exome AF: 0.706

Gnomad4 FIN exome AF: 0.462

Gnomad4 NFE exome AF: 0.421

Gnomad4 OTH exome AF: 0.514

GnomAD4 genome AF: 0.572 AC: 86968 AN: 152132 Hom.: 27315 Cov.: 33 AF XY: 0.581 AC XY: 43201 AN XY: 74372

Gnomad4 AFR AF: 0.781

Gnomad4 AMR AF: 0.619

Gnomad4 ASJ AF: 0.384

Gnomad4 EAS AF: 0.989

Gnomad4 SAS AF: 0.723

Gnomad4 FIN AF: 0.455

Gnomad4 NFE AF: 0.424

Gnomad4 OTH AF: 0.535

Alfa AF: 0.450 Hom.: 30335

Bravo AF: 0.589

Asia WGS AF: 0.842 AC: 2928 AN: 3478

EpiCase AF: 0.413

EpiControl AF: 0.403

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

May 09, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

May 07, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Glu149Glu in Exon 04 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 42.2% (2959/7020) of European American chromosomes from a broad population by the NHLBI Exome Sequen cing Project (http://evs.gs.washington.edu/EVS; dbSNP rs876305). -

Autosomal dominant nonsyndromic hearing loss 5 Benign:2

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	8.7
DANN	Benign	0.59

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: rs876305; hg19: chr7-24758795; COSMIC: COSV61651807; COSMIC: COSV61651807;