rs12540919

Positions:

chr7-24717332-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001127453.2(GSDME):c.619G>A(p.Val207Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0959 in 1,611,688 control chromosomes in the GnomAD database, including 7,711 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.082 ( 551 hom., cov: 31)

Exomes 𝑓: 0.097 ( 7160 hom. )

Consequence

GSDME
NM_001127453.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 2.73

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0017653406).

BP6

Variant 7-24717332-C-T is Benign according to our data. Variant chr7-24717332-C-T is described in ClinVar as [Benign]. Clinvar id is 44847.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-24717332-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.122 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GSDME	NM_001127453.2 linkuse as main transcript	c.619G>A	p.Val207Met	missense_variant	5/10	ENST00000645220.1	NP_001120925.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GSDME	ENST00000645220.1 linkuse as main transcript	c.619G>A	p.Val207Met	missense_variant	5/10		NM_001127453.2	ENSP00000494186	P1	O60443-1

Frequencies

GnomAD3 genomes

AF:

0.0816

AC:

12243

AN:

150068

Hom.:

552

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0485

Gnomad AMI

AF:

0.0844

Gnomad AMR

AF:

0.0755

Gnomad ASJ

AF:

0.0862

Gnomad EAS

AF:

0.130

Gnomad SAS

AF:

0.122

Gnomad FIN

AF:

0.0816

Gnomad MID

AF:

0.134

Gnomad NFE

AF:

0.0958

Gnomad OTH

AF:

0.0908

GnomAD3 exomes

AF:

0.0929

AC:

23342

AN:

251374

Hom.:

1152

AF XY:

0.0957

AC XY:

12997

AN XY:

135862

show subpopulations

Gnomad AFR exome

AF:

0.0460

Gnomad AMR exome

AF:

0.0786

Gnomad ASJ exome

AF:

0.0768

Gnomad EAS exome

AF:

0.130

Gnomad SAS exome

AF:

0.115

Gnomad FIN exome

AF:

0.0844

Gnomad NFE exome

AF:

0.0949

Gnomad OTH exome

AF:

0.0934

GnomAD4 exome

AF:

0.0973

AC:

142253

AN:

1461502

Hom.:

7160

Cov.:

AF XY:

0.0980

AC XY:

71253

AN XY:

727050

show subpopulations

Gnomad4 AFR exome

AF:

0.0435

Gnomad4 AMR exome

AF:

0.0770

Gnomad4 ASJ exome

AF:

0.0770

Gnomad4 EAS exome

AF:

0.135

Gnomad4 SAS exome

AF:

0.113

Gnomad4 FIN exome

AF:

0.0861

Gnomad4 NFE exome

AF:

0.0983

Gnomad4 OTH exome

AF:

0.0954

GnomAD4 genome

AF:

0.0815

AC:

12247

AN:

150186

Hom.:

551

Cov.:

AF XY:

0.0824

AC XY:

6031

AN XY:

73226

show subpopulations

Gnomad4 AFR

AF:

0.0484

Gnomad4 AMR

AF:

0.0755

Gnomad4 ASJ

AF:

0.0862

Gnomad4 EAS

AF:

0.130

Gnomad4 SAS

AF:

0.122

Gnomad4 FIN

AF:

0.0816

Gnomad4 NFE

AF:

0.0958

Gnomad4 OTH

AF:

0.0922

Alfa

AF:

0.0925

Hom.:

1553

Bravo

AF:

0.0785

TwinsUK

AF:

0.0963

AC:

357

ALSPAC

AF:

0.102

AC:

394

ESP6500AA

AF:

0.0490

AC:

216

ESP6500EA

AF:

0.0933

AC:

802

ExAC

AF:

0.0942

AC:

11432

Asia WGS

AF:

0.108

AC:

374

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	Val207Met in Exon 05 of DFNA5: This variant is not expected to have clinical sig nificance because it has been identified in 9.3% (654/7020) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs12540919). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 09, 2017	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. -

Autosomal dominant nonsyndromic hearing loss 5

Benign:1

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. -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.37

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.17

T;T;.;.;T;.

Eigen

Uncertain

0.46

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Benign

0.64

LIST_S2

Benign

0.72

.;.;.;T;T;T

MetaRNN

Benign

0.0018

T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationTaster

Benign

0.00090

P;P;P;P;P

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-0.86

N;.;N;N;N;.

REVEL

Benign

0.11

Sift

Benign

0.032

D;.;D;D;D;.

Sift4G

Uncertain

0.020

D;.;D;D;D;.

Polyphen

0.99

D;D;.;.;D;.

Vest4

0.51

MPC

0.26

ClinPred

0.062

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.041

gMVP

0.63

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over