7-24719199-G-T

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.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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P142A) has been classified as Uncertain significance.

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

Publications

42 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):

nonsyndromic genetic hearing loss
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
autosomal dominant nonsyndromic hearing loss 5
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
autosomal dominant nonsyndromic hearing loss
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

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=0.0027372837).

BP6

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

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.445 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	UniProt
GSDME	NM_001127453.2	MANE Select	c.424C>A	p.Pro142Thr	missense	Exon 4 of 10	NP_001120925.1	O60443-1
GSDME	NM_004403.3		c.424C>A	p.Pro142Thr	missense	Exon 4 of 10	NP_004394.1	O60443-1
GSDME	NM_001127454.2		c.-69C>A		5_prime_UTR	Exon 3 of 9	NP_001120926.1	O60443-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GSDME	ENST00000645220.1	MANE Select	c.424C>A	p.Pro142Thr	missense	Exon 4 of 10	ENSP00000494186.1	O60443-1
GSDME	ENST00000342947.9	TSL:1	c.424C>A	p.Pro142Thr	missense	Exon 4 of 10	ENSP00000339587.3	O60443-1
GSDME	ENST00000419307.6	TSL:1	c.-69C>A		5_prime_UTR	Exon 3 of 9	ENSP00000401332.1	O60443-3

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

GnomAD2 exomes

AF:

0.200

AC:

49879

AN:

249168

AF XY:

0.205

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 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

African (AFR)

AF:

0.207

AC:

6900

AN:

33360

American (AMR)

AF:

0.150

AC:

6723

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.108

AC:

2822

AN:

26116

East Asian (EAS)

AF:

0.438

AC:

17350

AN:

39654

South Asian (SAS)

AF:

0.324

AC:

27855

AN:

86052

European-Finnish (FIN)

AF:

0.173

AC:

8954

AN:

51696

Middle Eastern (MID)

AF:

0.160

AC:

914

AN:

5730

European-Non Finnish (NFE)

AF:

0.151

AC:

167271

AN:

1107496

Other (OTH)

AF:

0.182

AC:

10964

AN:

60182

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.400

Heterozygous variant carriers

11009

22018

33028

44037

55046

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

6236

12472

18708

24944

31180

<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:

0.181

AC:

27509

AN:

152144

Hom.:

2876

Cov.:

AF XY:

0.185

AC XY:

13757

AN XY:

74364

show subpopulations

African (AFR)

AF:

0.208

AC:

8641

AN:

41494

American (AMR)

AF:

0.140

AC:

2138

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.123

AC:

428

AN:

3472

East Asian (EAS)

AF:

0.461

AC:

2378

AN:

5162

South Asian (SAS)

AF:

0.327

AC:

1573

AN:

4816

European-Finnish (FIN)

AF:

0.166

AC:

1757

AN:

10588

Middle Eastern (MID)

AF:

0.151

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.148

AC:

10066

AN:

67994

Other (OTH)

AF:

0.178

AC:

375

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

1116

2232

3348

4464

5580

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

312

624

936

1248

1560

<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:

0.159

Hom.:

7081

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

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Autosomal dominant nonsyndromic hearing loss 5 (2)

not specified (2)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.69

BayesDel_noAF

Benign

-0.62

CADD

Benign

(source)

DANN

Benign

0.58

DEOGEN2

Benign

0.097

Eigen

Benign

-0.92

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.054

LIST_S2

Benign

0.57

MetaRNN

Benign

0.0027

MetaSVM

Benign

-0.93

PhyloP100

0.94

PrimateAI

Benign

0.31

PROVEAN

Benign

-1.7

REVEL

Benign

0.055

Sift

Benign

0.93

Sift4G

Benign

0.94

Polyphen

0.27

Vest4

0.057

MPC

0.050

ClinPred

0.026

GERP RS

0.25

PromoterAI

-0.012

Neutral

(source)

Varity_R

0.053

gMVP

0.27

Mutation Taster

=292/8

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

Computational scores

Splicing

Publications

Other links and lift over