chr7-24706376-A-G

Position:

chr7-24706376-A-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4BP6BS2

The NM_001127453.2(GSDME):c.991T>C(p.Cys331Arg) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000049 in 1,612,174 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000051 ( 1 hom. )

Consequence

GSDME
NM_001127453.2 missense, splice_region

Scores

Splicing: ADA: 0.0003805

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: 1.05

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 Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.32343775).

BP6

Variant 7-24706376-A-G is Benign according to our data. Variant chr7-24706376-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 179118.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.

BS2

High AC in GnomAdExome4 at 75 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GSDME	NM_001127453.2 linkuse as main transcript	c.991T>C	p.Cys331Arg	missense_variant, splice_region_variant	8/10	ENST00000645220.1	NP_001120925.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
GSDME	ENST00000645220.1 linkuse as main transcript	c.991T>C	p.Cys331Arg	missense_variant, splice_region_variant	8/10		NM_001127453.2	ENSP00000494186.1	O60443-1
GSDME	ENST00000342947.9 linkuse as main transcript	c.991T>C	p.Cys331Arg	missense_variant, splice_region_variant	8/10	1		ENSP00000339587.3	O60443-1
GSDME	ENST00000419307.6 linkuse as main transcript	c.499T>C	p.Cys167Arg	missense_variant, splice_region_variant	7/9	1		ENSP00000401332.1	O60443-3
GSDME	ENST00000409970.6 linkuse as main transcript	c.499T>C	p.Cys167Arg	missense_variant, splice_region_variant	7/9	5		ENSP00000387119.1	O60443-3

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000827

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000888

AC:

AN:

247630

Hom.:

AF XY:

0.000119

AC XY:

AN XY:

134358

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000722

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000514

AC:

AN:

1459868

Hom.:

Cov.:

AF XY:

0.0000661

AC XY:

AN XY:

726258

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000790

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.000116

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152306

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000827

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ExAC

AF:

0.0000659

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 15, 2013

Variant classified as Uncertain Significance - Favor Benign. The Cys331Arg varia nt in DFNA5 has not been previously reported in individuals with hearing loss an d frequency data from large population studies is insufficient. This variant is located in the first base of an exon though computational splicing tools do not predict altered splicing. Additional computational analyses (biochemical amino a cid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) do not provide str ong support for or against an impact of the amino acid change to the protein. Ad ditional data is needed to determine the clinical significance of this variant; however, the identification of this variant in a family with recessive hearing l oss due to GJB2 suggests that it is more likely benign given that pathogenic DFN A5 variants are dominant and to date only found to affect exon 8 splicing. -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 03, 2024

The c.991T>C (p.C331R) alteration is located in exon 8 (coding exon 7) of the DFNA5 gene. This alteration results from a T to C substitution at nucleotide position 991, causing the cysteine (C) at amino acid position 331 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Autosomal dominant nonsyndromic hearing loss 5

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Neuberg Centre For Genomic Medicine, NCGM

The missense, splice region variant c.991T>Cp.Cys331Arg in GSDME gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The variant has 0.01% allele freuency in gnomAD Exomes and is novel not in any individuals in 1000 Genomes. This variant has been reported to the ClinVar database as Uncertain Significance. The variant is predicted to be damaging by SIFT. The amino acid Cysteine at position 331 is changed to a Arginine changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Cys331Arg in GSDME is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 25, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.88

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.31

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.22

T;T;.;.;T

Eigen

Uncertain

0.27

Eigen_PC

Benign

0.16

FATHMM_MKL

Benign

0.64

LIST_S2

Benign

0.56

.;.;.;T;T

M_CAP

Benign

0.0079

MetaRNN

Benign

0.32

T;T;T;T;T

MetaSVM

Benign

-1.0

PrimateAI

Uncertain

0.56

PROVEAN

Uncertain

-3.5

D;.;D;D;D

REVEL

Benign

0.28

Sift

Uncertain

0.0060

D;.;D;D;D

Sift4G

Benign

0.12

T;.;T;T;T

Polyphen

1.0

D;D;.;.;D

Vest4

0.64

MutPred

0.66

Gain of disorder (P = 0.044);Gain of disorder (P = 0.044);.;.;Gain of disorder (P = 0.044);

MVP

0.41

MPC

0.24

ClinPred

0.46

GERP RS

2.5

Varity_R

0.47

gMVP

0.68

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00038

dbscSNV1_RF

Benign

0.016

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