NM_001127453.2:c.119dupA

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 8P and 9B. PVS1BP6BS1BS2

The NM_001127453.2(GSDME):c.119dupA(p.Lys41GlufsTer113) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00075 in 1,613,944 control chromosomes in the GnomAD database, including 16 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.00083 ( 2 hom., cov: 32)

Exomes 𝑓: 0.00074 ( 14 hom. )

Consequence

GSDME
NM_001127453.2 frameshift

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: 0.526

Publications

2 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: Likely_benign. The variant received -1 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

BP6

Variant 7-24749655-C-CT is Benign according to our data. Variant chr7-24749655-C-CT is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 228555. Variant chr7-24749655-C-CT is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 228555. Variant chr7-24749655-C-CT is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 228555. Variant chr7-24749655-C-CT is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 228555. Variant chr7-24749655-C-CT is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 228555. Variant chr7-24749655-C-CT is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 228555. Variant chr7-24749655-C-CT is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 228555. Variant chr7-24749655-C-CT is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 228555. Variant chr7-24749655-C-CT is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 228555. Variant chr7-24749655-C-CT is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 228555. Variant chr7-24749655-C-CT is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 228555. Variant chr7-24749655-C-CT is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 228555. Variant chr7-24749655-C-CT is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 228555. Variant chr7-24749655-C-CT is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 228555.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000835 (127/152160) while in subpopulation NFE AF = 0.000235 (16/68022). AF 95% confidence interval is 0.000147. There are 2 homozygotes in GnomAd4. There are 48 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 127 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GSDME	NM_001127453.2 link	c.119dupA	p.Lys41GlufsTer113	frameshift_variant	Exon 2 of 10	ENST00000645220.1	NP_001120925.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GSDME	ENST00000645220.1 link	c.119dupA	p.Lys41GlufsTer113	frameshift_variant	Exon 2 of 10		NM_001127453.2	ENSP00000494186.1		O60443-1

Frequencies

GnomAD3 genomes

AF:

0.000835

AC:

127

AN:

152160

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.0300

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000235

Gnomad OTH

AF:

0.000956

GnomAD2 exomes

AF:

0.00152

AC:

381

AN:

251436

AF XY:

0.00130

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.0320

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000360

Gnomad OTH exome

AF:

0.00261

GnomAD4 exome

AF:

0.000742

AC:

1084

AN:

1461784

Hom.:

Cov.:

AF XY:

0.000712

AC XY:

518

AN XY:

727200

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.0000224

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0297

AC:

775

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53388

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000159

AC:

177

AN:

1111938

Other (OTH)

AF:

0.00217

AC:

131

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

134

200

267

334

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.000835

AC:

127

AN:

152160

Hom.:

Cov.:

AF XY:

0.000646

AC XY:

AN XY:

74332

show subpopulations

African (AFR)

AF:

0.000121

AC:

AN:

41452

American (AMR)

AF:

0.00

AC:

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.0300

AC:

104

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5202

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000235

AC:

AN:

68022

Other (OTH)

AF:

0.000956

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00417

Hom.:

Bravo

AF:

0.000812

EpiCase

AF:

0.000436

EpiControl

AF:

0.000415

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:3

Mar 14, 2022

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

GSDME: BS1, BS2 -

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Uncertain:1

Nov 12, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant classified as Uncertain Significance - Favor Benign. The p.Lys41fs varia nt in DFNA5 has not been previously reported in individuals with hearing loss, b ut has been identified in 0.21% (137/66836) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs758488919 ). This variant is predicted to cause a frameshift, which alters the protein?s a mino acid sequence beginning at position 41 and leads to a premature termination codon 113 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. However, only variants resulting in altered splic ing and skipping of exon 8 have been reported to be causative for hearing loss t hrough a gain of function mechanism of disease (Van Laer 2004). The p.Lys41fs va riant is located in exon 2 of DFNA5 and is expected to result in loss of functio n (LoF), which is not a known mechanism of hearing loss in this gene. In fact, a frameshift variant in DFNA5 has been reported in members of an Iranian family, in which the variant did not segregate with the hearing loss (Van Laer 2007). In summary, while the clinical significance of the p.Lys41fs variant is uncertain, its frequency in the general population and the lack of evidence supporting a L oF mechanism for hearing loss in DFNA5 suggests it is more likely to be benign. -

Nonsyndromic genetic hearing loss

Benign:1

Jul 15, 2021

INGEBI, INGEBI / CONICET

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Based on ACMG/AMP guidelines and Hearing Loss Expert Panel specific criteria: The filter allele frequency of c.119dupA in DFNA5 gene is 2.9% (330/10368 with 95%CI) in Ashkenazi Jewish population in gnomad database, exceeding the treshold for autosomal dominant non-syndromic hearing loss stablished by the Hearing Loss Expert Panel group, meeting BA1. Although c.119dup is a frameshift variant (p.Lys41Glufs*113), it was reported that DFNA5-associated hearing loss is caused by a gain-of-function and not haplo-insufficiency (PMID:15173223, 7427029). Therefore PVS1 is not applied. In this report, c.119dupA was a confirmed de novo occurence identified in a sporadic congenital moderate non-syndromic hearing loss patient, meeting PS2. Considering BA1 and PS2, the variant is classifie as Benign. -

GSDME-related disorder

Benign:1

Mar 12, 2020

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.53

Mutation Taster

=172/28

disease causing (fs/PTC)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over