NM_001127453.2:c.405-15G>A

Variant names:

• chr7-24719233-C-T
• rs754553
• NM_001127453.2:c.405-15G>A

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 17 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 -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 VariationId is 44842.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
GSDME	NM_001127453.2	c.405-15G>A		intron_variant	Intron 3 of 9	ENST00000645220.1	NP_001120925.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GSDME	ENST00000645220.1	c.405-15G>A		intron_variant	Intron 3 of 9		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

GnomAD2 exomes AF: 0.200 AC: 48731 AN: 243396 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: 0.458

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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.206 AC: 6852 AN: 33268

American (AMR) AF: 0.150 AC: 6703 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.108 AC: 2808 AN: 26090

East Asian (EAS) AF: 0.437 AC: 17316 AN: 39604

South Asian (SAS) AF: 0.323 AC: 27770 AN: 85902

European-Finnish (FIN) AF: 0.170 AC: 7959 AN: 46816

Middle Eastern (MID) AF: 0.159 AC: 907 AN: 5710

European-Non Finnish (NFE) AF: 0.150 AC: 165389 AN: 1103968

Other (OTH) AF: 0.181 AC: 10891 AN: 60042

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

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

African (AFR) AF: 0.208 AC: 8638 AN: 41484

American (AMR) AF: 0.140 AC: 2133 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.123 AC: 428 AN: 3472

East Asian (EAS) AF: 0.462 AC: 2385 AN: 5164

South Asian (SAS) AF: 0.326 AC: 1573 AN: 4820

European-Finnish (FIN) AF: 0.166 AC: 1760 AN: 10576

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

European-Non Finnish (NFE) AF: 0.148 AC: 10062 AN: 68010

Other (OTH) AF: 0.178 AC: 375 AN: 2112

Alfa AF: 0.121 Hom.: 378

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

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:2

Jun 24, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

May 07, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		-2.4
PromoterAI		-0.070	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs754553; hg19: chr7-24758852; COSMIC: COSV61651769; COSMIC: COSV61651769;