dbSNP rs71535705: GSDME:p.Ala400Val (chr7-24702818-G-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_004403.3(GSDME):c.1199C>T(p.Ala400Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0201 in 1,612,940 control chromosomes in the GnomAD database, including 442 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A400T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.017 ( 31 hom., cov: 33)

Exomes 𝑓: 0.020 ( 411 hom. )

Consequence

GSDME
NM_004403.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.06

Publications

7 publications found

Variant links:

COSMIC-nc: COSV107436142

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=0.002800405).

BP6

Variant 7-24702818-G-A is Benign according to our data. Variant chr7-24702818-G-A is described in ClinVar as Benign. ClinVar VariationId is 44839.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0166 (2522/152322) while in subpopulation NFE AF = 0.0265 (1803/68038). AF 95% confidence interval is 0.0255. There are 31 homozygotes in GnomAd4. There are 1205 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 2522 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004403.3. 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.1199C>T	p.Ala400Val	missense	Exon 9 of 10	NP_001120925.1
GSDME	NM_004403.3		c.1199C>T	p.Ala400Val	missense	Exon 9 of 10	NP_004394.1
GSDME	NM_001127454.2		c.707C>T	p.Ala236Val	missense	Exon 8 of 9	NP_001120926.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
GSDME	ENST00000645220.1	MANE Select	c.1199C>T	p.Ala400Val	missense	Exon 9 of 10	ENSP00000494186.1
GSDME	ENST00000342947.9	TSL:1	c.1199C>T	p.Ala400Val	missense	Exon 9 of 10	ENSP00000339587.3
GSDME	ENST00000419307.6	TSL:1	c.707C>T	p.Ala236Val	missense	Exon 8 of 9	ENSP00000401332.1

Frequencies

GnomAD3 genomes

AF:

0.0166

AC:

2522

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00410

Gnomad AMI

AF:

0.0462

Gnomad AMR

AF:

0.0141

Gnomad ASJ

AF:

0.00432

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00269

Gnomad FIN

AF:

0.0221

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0265

Gnomad OTH

AF:

0.0134

GnomAD2 exomes

AF:

0.0162

AC:

4084

AN:

251438

AF XY:

0.0160

show subpopulations

Gnomad AFR exome

AF:

0.00271

Gnomad AMR exome

AF:

0.0106

Gnomad ASJ exome

AF:

0.00417

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.0239

Gnomad NFE exome

AF:

0.0255

Gnomad OTH exome

AF:

0.0182

GnomAD4 exome

AF:

0.0205

AC:

29913

AN:

1460618

Hom.:

411

Cov.:

AF XY:

0.0203

AC XY:

14721

AN XY:

726592

show subpopulations

African (AFR)

AF:

0.00263

AC:

AN:

33454

American (AMR)

AF:

0.0110

AC:

490

AN:

44690

Ashkenazi Jewish (ASJ)

AF:

0.00441

AC:

115

AN:

26100

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39640

South Asian (SAS)

AF:

0.00323

AC:

278

AN:

86192

European-Finnish (FIN)

AF:

0.0259

AC:

1377

AN:

53256

Middle Eastern (MID)

AF:

0.00243

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

0.0238

AC:

26420

AN:

1111202

Other (OTH)

AF:

0.0187

AC:

1130

AN:

60328

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.449

Heterozygous variant carriers

1519

3038

4558

6077

7596

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

900

1800

2700

3600

4500

<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:

0.0166

AC:

2522

AN:

152322

Hom.:

Cov.:

AF XY:

0.0162

AC XY:

1205

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.00409

AC:

170

AN:

41564

American (AMR)

AF:

0.0140

AC:

215

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00432

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5186

South Asian (SAS)

AF:

0.00269

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.0221

AC:

235

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0265

AC:

1803

AN:

68038

Other (OTH)

AF:

0.0132

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

134

268

401

535

669

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

150

<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:

0.0223

Hom.:

149

Bravo

AF:

0.0147

TwinsUK

AF:

0.0232

AC:

ALSPAC

AF:

0.0231

AC:

ESP6500AA

AF:

0.00318

AC:

ESP6500EA

AF:

0.0228

AC:

196

ExAC

AF:

0.0171

AC:

2080

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.0232

EpiControl

AF:

0.0221

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Autosomal dominant nonsyndromic hearing loss 5 (2)

not provided (2)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.62

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.063

Eigen

Benign

-0.73

Eigen_PC

Benign

-0.73

FATHMM_MKL

Benign

0.18

LIST_S2

Benign

0.62

MetaRNN

Benign

0.0028

MetaSVM

Benign

-1.0

PhyloP100

2.1

PrimateAI

Benign

0.34

PROVEAN

Benign

-1.3

REVEL

Benign

0.068

Sift

Benign

0.055

Sift4G

Benign

0.095

Polyphen

0.059

Vest4

0.20

MPC

0.047

ClinPred

0.0050

GERP RS

1.9

Varity_R

0.022

gMVP

0.25

Mutation Taster

=97/3

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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