7-24719199-G-T

Position:

chr7-24719199-G-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.424C>A(p.Pro142Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.173 in 1,607,152 control chromosomes in the GnomAD database, including 27,765 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.18 ( 2876 hom., cov: 32)

Exomes 𝑓: 0.17 ( 24889 hom. )

Consequence

GSDME
NM_001127453.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.943

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:

GSDME (HGNC:):

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=0.0027372837).

BP6

Variant 7-24719199-G-T is Benign according to our data. Variant chr7-24719199-G-T is described in ClinVar as [Benign]. Clinvar id is 44843.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-24719199-G-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.445 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.424C>A	p.Pro142Thr	missense_variant	4/10	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.424C>A	p.Pro142Thr	missense_variant	4/10		NM_001127453.2	ENSP00000494186.1		O60443-1

Frequencies

GnomAD3 genomes

AF:

0.181

AC:

27476

AN:

152026

Hom.:

2870

Cov.:

show subpopulations

Gnomad AFR

AF:

0.208

Gnomad AMI

AF:

0.120

Gnomad AMR

AF:

0.140

Gnomad ASJ

AF:

0.123

Gnomad EAS

AF:

0.461

Gnomad SAS

AF:

0.327

Gnomad FIN

AF:

0.166

Gnomad MID

AF:

0.153

Gnomad NFE

AF:

0.148

Gnomad OTH

AF:

0.170

GnomAD3 exomes

AF:

0.200

AC:

49879

AN:

249168

Hom.:

6209

AF XY:

0.205

AC XY:

27695

AN XY:

134814

show subpopulations

Gnomad AFR exome

AF:

0.208

Gnomad AMR exome

AF:

0.154

Gnomad ASJ exome

AF:

0.108

Gnomad EAS exome

AF:

0.459

Gnomad SAS exome

AF:

0.329

Gnomad FIN exome

AF:

0.169

Gnomad NFE exome

AF:

0.151

Gnomad OTH exome

AF:

0.172

GnomAD4 exome

AF:

0.172

AC:

249753

AN:

1455008

Hom.:

24889

Cov.:

AF XY:

0.176

AC XY:

127500

AN XY:

724134

show subpopulations

Gnomad4 AFR exome

AF:

0.207

Gnomad4 AMR exome

AF:

0.150

Gnomad4 ASJ exome

AF:

0.108

Gnomad4 EAS exome

AF:

0.438

Gnomad4 SAS exome

AF:

0.324

Gnomad4 FIN exome

AF:

0.173

Gnomad4 NFE exome

AF:

0.151

Gnomad4 OTH exome

AF:

0.182

GnomAD4 genome

AF:

0.181

AC:

27509

AN:

152144

Hom.:

2876

Cov.:

AF XY:

0.185

AC XY:

13757

AN XY:

74364

show subpopulations

Gnomad4 AFR

AF:

0.208

Gnomad4 AMR

AF:

0.140

Gnomad4 ASJ

AF:

0.123

Gnomad4 EAS

AF:

0.461

Gnomad4 SAS

AF:

0.327

Gnomad4 FIN

AF:

0.166

Gnomad4 NFE

AF:

0.148

Gnomad4 OTH

AF:

0.178

Alfa

AF:

0.154

Hom.:

4274

Bravo

AF:

0.179

TwinsUK

AF:

0.154

AC:

571

ALSPAC

AF:

0.160

AC:

618

ESP6500AA

AF:

0.210

AC:

925

ESP6500EA

AF:

0.143

AC:

1230

ExAC

AF:

0.205

AC:

24935

Asia WGS

AF:

0.380

AC:

1321

AN:

3478

EpiCase

AF:

0.147

EpiControl

AF:

0.143

ClinVar

Significance: Benign

Submissions summary: Benign:5

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	Pro142Thr in Exon 04 of DFNA5: This variant is not expected to have clinical sig nificance because it has been identified in 21.1% (788/3738) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs754554). -
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:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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

0.10

BayesDel_addAF

Benign

-0.69

BayesDel_noAF

Benign

-0.62

CADD

Benign

DANN

Benign

0.58

DEOGEN2

Benign

0.097

T;T;T;.

Eigen

Benign

-0.92

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.054

LIST_S2

Benign

0.57

.;.;T;T

MetaRNN

Benign

0.0027

T;T;T;T

MetaSVM

Benign

-0.93

PrimateAI

Benign

0.31

PROVEAN

Benign

-1.7

N;.;N;.

REVEL

Benign

0.055

Sift

Benign

0.93

T;.;T;.

Sift4G

Benign

0.94

T;.;T;.

Polyphen

0.27

B;B;B;.

Vest4

0.057

MPC

0.050

ClinPred

0.026

GERP RS

0.25

Varity_R

0.053

gMVP

0.27

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