NM_001127453.2:c.1199C>T

Variant names:

• chr7-24702818-G-A
• rs71535705
• NM_001127453.2:c.1199C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001127453.2(GSDME):​c.1199C>T​(p.Ala400Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0201 in 1,612,940 control chromosomes in the GnomAD database, including 442 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A400T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.017 (31 hom., cov: 33)
  • Exomes 𝑓: 0.020 (411 hom.)
• Consequence: GSDME NM_001127453.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 2.06
• Publications: 7 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=0.002800405).
• BP6: Variant 7-24702818-G-A is Benign according to our data. Variant chr7-24702818-G-A is described in ClinVar as Benign. ClinVar VariationId is 44839.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0166 (2522/152322) while in subpopulation NFE AF = 0.0265 (1803/68038). AF 95% confidence interval is 0.0255. There are 31 homozygotes in GnomAd4. There are 1205 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2522 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GSDME	NM_001127453.2	c.1199C>T	p.Ala400Val	missense_variant	Exon 9 of 10	ENST00000645220.1	NP_001120925.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GSDME	ENST00000645220.1	c.1199C>T	p.Ala400Val	missense_variant	Exon 9 of 10		NM_001127453.2	ENSP00000494186.1

Frequencies

GnomAD3 genomes AF: 0.0166 AC: 2522 AN: 152204 Hom.: 31 Cov.: 33

Gnomad AFR AF: 0.00410

Gnomad AMI AF: 0.0462

Gnomad AMR AF: 0.0141

Gnomad ASJ AF: 0.00432

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.0221

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0265

Gnomad OTH AF: 0.0134

GnomAD2 exomes AF: 0.0162 AC: 4084 AN: 251438 AF XY: 0.0160

Gnomad AFR exome AF: 0.00271

Gnomad AMR exome AF: 0.0106

Gnomad ASJ exome AF: 0.00417

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0239

Gnomad NFE exome AF: 0.0255

Gnomad OTH exome AF: 0.0182

GnomAD4 exome AF: 0.0205 AC: 29913 AN: 1460618 Hom.: 411 Cov.: 31 AF XY: 0.0203 AC XY: 14721 AN XY: 726592

African (AFR) AF: 0.00263 AC: 88 AN: 33454

American (AMR) AF: 0.0110 AC: 490 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.00441 AC: 115 AN: 26100

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39640

South Asian (SAS) AF: 0.00323 AC: 278 AN: 86192

European-Finnish (FIN) AF: 0.0259 AC: 1377 AN: 53256

Middle Eastern (MID) AF: 0.00243 AC: 14 AN: 5756

European-Non Finnish (NFE) AF: 0.0238 AC: 26420 AN: 1111202

Other (OTH) AF: 0.0187 AC: 1130 AN: 60328

GnomAD4 genome AF: 0.0166 AC: 2522 AN: 152322 Hom.: 31 Cov.: 33 AF XY: 0.0162 AC XY: 1205 AN XY: 74476

African (AFR) AF: 0.00409 AC: 170 AN: 41564

American (AMR) AF: 0.0140 AC: 215 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00432 AC: 15 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5186

South Asian (SAS) AF: 0.00269 AC: 13 AN: 4824

European-Finnish (FIN) AF: 0.0221 AC: 235 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0265 AC: 1803 AN: 68038

Other (OTH) AF: 0.0132 AC: 28 AN: 2116

Alfa AF: 0.0223 Hom.: 149

Bravo AF: 0.0147

TwinsUK AF: 0.0232 AC: 86

ALSPAC AF: 0.0231 AC: 89

ESP6500AA AF: 0.00318 AC: 14

ESP6500EA AF: 0.0228 AC: 196

ExAC AF: 0.0171 AC: 2080

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.0232

EpiControl AF: 0.0221

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 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. -

Nov 29, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

Jun 14, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 20, 2018

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. -

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

Ala400Val in Exon 09 of DFNA5: This variant is not expected to have clinical sig nificance because it has been identified in 2.3% (163/7020) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs71535705). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	15
DANN	Benign	0.97
DEOGEN2	Benign	0.063	T;T;.;.;T;.
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.73
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.62	.;.;.;T;T;T
MetaRNN	Benign	0.0028	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
PhyloP100		2.1
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.3	N;.;N;N;N;D
REVEL	Benign	0.068
Sift	Benign	0.055	T;.;D;D;T;D
Sift4G	Benign	0.095	T;.;T;T;T;T
Polyphen		0.059	B;B;.;.;B;.
Vest4		0.20
MPC		0.047
ClinPred		0.0050	T
GERP RS		1.9
Varity_R		0.022
gMVP		0.25
Mutation Taster		=97/3	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs71535705; hg19: chr7-24742437; COSMIC: COSV107436142;