rs71535705

chr7-24702818-G-A

Variant summary

Our verdict is Benign. Variant got -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. 11/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Benignin 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

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 -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 id is 44839.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-24702818-G-A is described in Lovd as [Likely_benign].
• 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 male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 2522 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GSDME	NM_001127453.2	c.1199C>T	p.Ala400Val	missense_variant	9/10	ENST00000645220.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GSDME	ENST00000645220.1	c.1199C>T	p.Ala400Val	missense_variant	9/10		NM_001127453.2	P1

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

GnomAD3 exomes AF: 0.0162 AC: 4084 AN: 251438 Hom.: 50 AF XY: 0.0160 AC XY: 2171 AN XY: 135888

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 SAS exome AF: 0.00323

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

Gnomad4 AFR exome AF: 0.00263

Gnomad4 AMR exome AF: 0.0110

Gnomad4 ASJ exome AF: 0.00441

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00323

Gnomad4 FIN exome AF: 0.0259

Gnomad4 NFE exome AF: 0.0238

Gnomad4 OTH exome AF: 0.0187

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

Gnomad4 AFR AF: 0.00409

Gnomad4 AMR AF: 0.0140

Gnomad4 ASJ AF: 0.00432

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00269

Gnomad4 FIN AF: 0.0221

Gnomad4 NFE AF: 0.0265

Gnomad4 OTH AF: 0.0132

Alfa AF: 0.0219 Hom.: 66

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

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jun 14, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 20, 2018	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

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 07, 2012

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
MetaRNN	Benign	0.0028	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N;N;N
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs71535705; hg19: chr7-24742437;