rs12540919

Variant names:

Variant summary

Our verdict is Benign. The variant received -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

Publications

33 publications found

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 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

GSDME links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 44847.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001127453.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
GSDME	NM_001127453.2	MANE Select	c.619G>A	p.Val207Met	missense	Exon 5 of 10	NP_001120925.1
GSDME	NM_004403.3		c.619G>A	p.Val207Met	missense	Exon 5 of 10	NP_004394.1
GSDME	NM_001127454.2		c.127G>A	p.Val43Met	missense	Exon 4 of 9	NP_001120926.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
GSDME	ENST00000645220.1	MANE Select	c.619G>A	p.Val207Met	missense	Exon 5 of 10	ENSP00000494186.1
GSDME	ENST00000342947.9	TSL:1	c.619G>A	p.Val207Met	missense	Exon 5 of 10	ENSP00000339587.3
GSDME	ENST00000419307.6	TSL:1	c.127G>A	p.Val43Met	missense	Exon 4 of 9	ENSP00000401332.1

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

GnomAD2 exomes

AF:

0.0929

AC:

23342

AN:

251374

AF XY:

0.0957

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 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

African (AFR)

AF:

0.0435

AC:

1455

AN:

33478

American (AMR)

AF:

0.0770

AC:

3441

AN:

44694

Ashkenazi Jewish (ASJ)

AF:

0.0770

AC:

2011

AN:

26130

East Asian (EAS)

AF:

0.135

AC:

5343

AN:

39660

South Asian (SAS)

AF:

0.113

AC:

9778

AN:

86250

European-Finnish (FIN)

AF:

0.0861

AC:

4596

AN:

53384

Middle Eastern (MID)

AF:

0.110

AC:

636

AN:

5764

European-Non Finnish (NFE)

AF:

0.0983

AC:

109232

AN:

1111768

Other (OTH)

AF:

0.0954

AC:

5761

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

8393

16785

25178

33570

41963

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4042

8084

12126

16168

20210

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0815

AC:

12247

AN:

150186

Hom.:

551

Cov.:

AF XY:

0.0824

AC XY:

6031

AN XY:

73226

show subpopulations

African (AFR)

AF:

0.0484

AC:

1992

AN:

41146

American (AMR)

AF:

0.0755

AC:

1121

AN:

14842

Ashkenazi Jewish (ASJ)

AF:

0.0862

AC:

296

AN:

3434

East Asian (EAS)

AF:

0.130

AC:

661

AN:

5080

South Asian (SAS)

AF:

0.122

AC:

570

AN:

4654

European-Finnish (FIN)

AF:

0.0816

AC:

843

AN:

10328

Middle Eastern (MID)

AF:

0.129

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0958

AC:

6457

AN:

67414

Other (OTH)

AF:

0.0922

AC:

192

AN:

2082

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

581

1162

1744

2325

2906

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

146

292

438

584

730

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0906

Hom.:

2875

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

May 07, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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).

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.

Autosomal dominant nonsyndromic hearing loss 5

Benign:1

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.

not provided

Benign:1

Feb 01, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.37

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.17

Eigen

Uncertain

0.46

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Benign

0.64

LIST_S2

Benign

0.72

MetaRNN

Benign

0.0018

MetaSVM

Benign

-1.1

PhyloP100

2.7

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-0.86

REVEL

Benign

0.11

Sift

Benign

0.032

Sift4G

Uncertain

0.020

Polyphen

0.99

Vest4

0.51

MPC

0.26

ClinPred

0.062

GERP RS

4.8

PromoterAI

0.089

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.041

gMVP

0.63

Mutation Taster

=98/2

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over