Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4BP6BS1BS2

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). Synonymous variant affecting the same amino acid position (i.e. C331C) has been classified as Uncertain significance.

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

Publications

0 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: Benign. The variant received -10 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 VariationId is 179118.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0000263 (4/152306) while in subpopulation SAS AF = 0.000827 (4/4834). AF 95% confidence interval is 0.000282. There are 0 homozygotes in GnomAd4. There are 2 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAdExome4 at 75 AD gene.

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
GSDME	NM_001127453.2	MANE Select	c.991T>C	p.Cys331Arg	missense splice_region	Exon 8 of 10	NP_001120925.1
GSDME	NM_004403.3		c.991T>C	p.Cys331Arg	missense splice_region	Exon 8 of 10	NP_004394.1
GSDME	NM_001127454.2		c.499T>C	p.Cys167Arg	missense splice_region	Exon 7 of 9	NP_001120926.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
GSDME	ENST00000645220.1	MANE Select	c.991T>C	p.Cys331Arg	missense splice_region	Exon 8 of 10	ENSP00000494186.1
GSDME	ENST00000342947.9	TSL:1	c.991T>C	p.Cys331Arg	missense splice_region	Exon 8 of 10	ENSP00000339587.3
GSDME	ENST00000419307.6	TSL:1	c.499T>C	p.Cys167Arg	missense splice_region	Exon 7 of 9	ENSP00000401332.1

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

GnomAD2 exomes

AF:

0.0000888

AC:

AN:

247630

AF XY:

0.000119

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 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

African (AFR)

AF:

0.00

AC:

AN:

33414

American (AMR)

AF:

0.00

AC:

AN:

44680

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26116

East Asian (EAS)

AF:

0.00

AC:

AN:

39676

South Asian (SAS)

AF:

0.000790

AC:

AN:

86090

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53380

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4516

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111774

Other (OTH)

AF:

0.000116

AC:

AN:

60222

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152306

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74480

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41568

American (AMR)

AF:

0.00

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.000827

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68014

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.563

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.00

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000659

AC:

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Autosomal dominant nonsyndromic hearing loss 5 (1)

Inborn genetic diseases (1)

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.88

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.31

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.22

Eigen

Uncertain

0.27

Eigen_PC

Benign

0.16

FATHMM_MKL

Benign

0.64

LIST_S2

Benign

0.56

M_CAP

Benign

0.0079

MetaRNN

Benign

0.32

MetaSVM

Benign

-1.0

PhyloP100

1.1

PrimateAI

Uncertain

0.56

PROVEAN

Uncertain

-3.5

REVEL

Benign

0.28

Sift

Uncertain

0.0060

Sift4G

Benign

0.12

Polyphen

1.0

Vest4

0.64

MutPred

0.66

Gain of disorder (P = 0.044)

MVP

0.41

MPC

0.24

ClinPred

0.46

GERP RS

2.5

PromoterAI

0.038

Neutral

(source)

Varity_R

0.47

gMVP

0.68

Mutation Taster

=70/30

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

rs373787249

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

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over