7-24719134-C-T

Variant names:

• chr7-24719134-C-T
• rs754555
• NM_001127453.2:c.489G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001127453.2(GSDME):​c.489G>A​(p.Thr163Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.174 in 1,613,482 control chromosomes in the GnomAD database, including 27,809 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (2874 hom., cov: 33)
  • Exomes 𝑓: 0.17 (24935 hom.)
• Consequence: GSDME NM_001127453.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.510
• Publications: 35 publications found

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 Gene-Disease associations (from GenCC):

• autosomal dominant nonsyndromic hearing loss

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• autosomal dominant nonsyndromic hearing loss 5

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 7-24719134-C-T is Benign according to our data. Variant chr7-24719134-C-T is described in ClinVar as Benign. ClinVar VariationId is 44845.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.51 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.445 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GSDME	NM_001127453.2	c.489G>A	p.Thr163Thr	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.489G>A	p.Thr163Thr	synonymous_variant	Exon 4 of 10		NM_001127453.2	ENSP00000494186.1

Frequencies

GnomAD3 genomes AF: 0.181 AC: 27464 AN: 152048 Hom.: 2868 Cov.: 33

Gnomad AFR AF: 0.208

Gnomad AMI AF: 0.120

Gnomad AMR AF: 0.140

Gnomad ASJ AF: 0.123

Gnomad EAS AF: 0.460

Gnomad SAS AF: 0.326

Gnomad FIN AF: 0.166

Gnomad MID AF: 0.155

Gnomad NFE AF: 0.148

Gnomad OTH AF: 0.171

GnomAD2 exomes AF: 0.200 AC: 50180 AN: 250932 AF XY: 0.205

Gnomad AFR exome AF: 0.208

Gnomad AMR exome AF: 0.154

Gnomad ASJ exome AF: 0.108

Gnomad EAS exome AF: 0.457

Gnomad FIN exome AF: 0.170

Gnomad NFE exome AF: 0.151

Gnomad OTH exome AF: 0.172

GnomAD4 exome AF: 0.173 AC: 252512 AN: 1461316 Hom.: 24935 Cov.: 52 AF XY: 0.177 AC XY: 128780 AN XY: 727006

African (AFR) AF: 0.208 AC: 6959 AN: 33476

American (AMR) AF: 0.150 AC: 6715 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.108 AC: 2833 AN: 26136

East Asian (EAS) AF: 0.437 AC: 17357 AN: 39700

South Asian (SAS) AF: 0.324 AC: 27986 AN: 86246

European-Finnish (FIN) AF: 0.174 AC: 9267 AN: 53138

Middle Eastern (MID) AF: 0.160 AC: 911 AN: 5684

European-Non Finnish (NFE) AF: 0.152 AC: 169428 AN: 1111836

Other (OTH) AF: 0.183 AC: 11056 AN: 60378

GnomAD4 genome AF: 0.181 AC: 27497 AN: 152166 Hom.: 2874 Cov.: 33 AF XY: 0.185 AC XY: 13744 AN XY: 74364

African (AFR) AF: 0.208 AC: 8642 AN: 41516

American (AMR) AF: 0.140 AC: 2136 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.123 AC: 428 AN: 3470

East Asian (EAS) AF: 0.460 AC: 2376 AN: 5164

South Asian (SAS) AF: 0.326 AC: 1568 AN: 4814

European-Finnish (FIN) AF: 0.166 AC: 1753 AN: 10582

Middle Eastern (MID) AF: 0.153 AC: 45 AN: 294

European-Non Finnish (NFE) AF: 0.148 AC: 10064 AN: 68004

Other (OTH) AF: 0.178 AC: 376 AN: 2112

Alfa AF: 0.159 Hom.: 3865

Bravo AF: 0.179

Asia WGS AF: 0.379 AC: 1319 AN: 3478

EpiCase AF: 0.147

EpiControl AF: 0.143

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

Thr163Thr 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 21.1% (788/3738) of African American chromosomes from a broad population by the NHLBI Exome Sequenci ng Project (http://evs.gs.washington.edu/EVS; dbSNP rs754555). -

Autosomal dominant nonsyndromic hearing loss 5 Benign:2

Jan 12, 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. -

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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	-0.55
CADD	Benign	9.6
DANN	Benign	0.66
PhyloP100		0.51
PromoterAI		-0.044	Neutral
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs754555; hg19: chr7-24758753; COSMIC: COSV61651115; COSMIC: COSV61651115;