chr7-24719199-G-T

Variant names:

• chr7-24719199-G-T
• rs754554
• NM_001127453.2:c.424C>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.424C>A​(p.Pro142Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.173 in 1,607,152 control chromosomes in the GnomAD database, including 27,765 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P142A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.18 (2876 hom., cov: 32)
  • Exomes 𝑓: 0.17 (24889 hom.)
• Consequence: GSDME NM_001127453.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.943
• Publications: 42 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 (MetaRNN=0.0027372837).
• BP6: Variant 7-24719199-G-T is Benign according to our data. Variant chr7-24719199-G-T is described in ClinVar as Benign. ClinVar VariationId is 44843.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.445 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GSDME	NM_001127453.2	c.424C>A	p.Pro142Thr	missense_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.424C>A	p.Pro142Thr	missense_variant	Exon 4 of 10		NM_001127453.2	ENSP00000494186.1

Frequencies

GnomAD3 genomes AF: 0.181 AC: 27476 AN: 152026 Hom.: 2870 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: 0.461

Gnomad SAS AF: 0.327

Gnomad FIN AF: 0.166

Gnomad MID AF: 0.153

Gnomad NFE AF: 0.148

Gnomad OTH AF: 0.170

GnomAD2 exomes AF: 0.200 AC: 49879 AN: 249168 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: 0.459

Gnomad FIN exome AF: 0.169

Gnomad NFE exome AF: 0.151

Gnomad OTH exome AF: 0.172

GnomAD4 exome AF: 0.172 AC: 249753 AN: 1455008 Hom.: 24889 Cov.: 36 AF XY: 0.176 AC XY: 127500 AN XY: 724134

African (AFR) AF: 0.207 AC: 6900 AN: 33360

American (AMR) AF: 0.150 AC: 6723 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.108 AC: 2822 AN: 26116

East Asian (EAS) AF: 0.438 AC: 17350 AN: 39654

South Asian (SAS) AF: 0.324 AC: 27855 AN: 86052

European-Finnish (FIN) AF: 0.173 AC: 8954 AN: 51696

Middle Eastern (MID) AF: 0.160 AC: 914 AN: 5730

European-Non Finnish (NFE) AF: 0.151 AC: 167271 AN: 1107496

Other (OTH) AF: 0.182 AC: 10964 AN: 60182

GnomAD4 genome AF: 0.181 AC: 27509 AN: 152144 Hom.: 2876 Cov.: 32 AF XY: 0.185 AC XY: 13757 AN XY: 74364

African (AFR) AF: 0.208 AC: 8641 AN: 41494

American (AMR) AF: 0.140 AC: 2138 AN: 15302

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

East Asian (EAS) AF: 0.461 AC: 2378 AN: 5162

South Asian (SAS) AF: 0.327 AC: 1573 AN: 4816

European-Finnish (FIN) AF: 0.166 AC: 1757 AN: 10588

Middle Eastern (MID) AF: 0.151 AC: 44 AN: 292

European-Non Finnish (NFE) AF: 0.148 AC: 10066 AN: 67994

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

Alfa AF: 0.159 Hom.: 7081

Bravo AF: 0.179

TwinsUK AF: 0.154 AC: 571

ALSPAC AF: 0.160 AC: 618

ESP6500AA AF: 0.210 AC: 925

ESP6500EA AF: 0.143 AC: 1230

ExAC AF: 0.205 AC: 24935

Asia WGS AF: 0.380 AC: 1321 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

Pro142Thr in Exon 04 of DFNA5: This variant is not expected to have clinical sig nificance because it has been identified in 21.1% (788/3738) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs754554). -

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
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	12
DANN	Benign	0.58
DEOGEN2	Benign	0.097	T;T;T;.
Eigen	Benign	-0.92
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.054	N
LIST_S2	Benign	0.57	.;.;T;T
MetaRNN	Benign	0.0027	T;T;T;T
MetaSVM	Benign	-0.93	T
PhyloP100		0.94
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.7	N;.;N;.
REVEL	Benign	0.055
Sift	Benign	0.93	T;.;T;.
Sift4G	Benign	0.94	T;.;T;.
Polyphen		0.27	B;B;B;.
Vest4		0.057
MPC		0.050
ClinPred		0.026	T
GERP RS		0.25
PromoterAI		-0.012	Neutral
Varity_R		0.053
gMVP		0.27
Mutation Taster		=292/8	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: rs754554; hg19: chr7-24758818; COSMIC: COSV61650801; COSMIC: COSV61650801;