Genetic Variant GSDME:c.-46A>T (chr7-24719176-T-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001127454.2(GSDME):c.-46A>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

GSDME
NM_001127454.2 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.873

Publications

36 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001127454.2. 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.447A>T	p.Glu149Asp	missense	Exon 4 of 10	NP_001120925.1	O60443-1
GSDME	NM_001127454.2		c.-46A>T		5_prime_UTR_premature_start_codon_gain	Exon 3 of 9	NP_001120926.1	O60443-3
GSDME	NM_001438059.1		c.-46A>T		5_prime_UTR_premature_start_codon_gain	Exon 3 of 9	NP_001424988.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GSDME	ENST00000419307.6	TSL:1	c.-46A>T		5_prime_UTR_premature_start_codon_gain	Exon 3 of 9	ENSP00000401332.1	O60443-3
GSDME	ENST00000645220.1	MANE Select	c.447A>T	p.Glu149Asp	missense	Exon 4 of 10	ENSP00000494186.1	O60443-1
GSDME	ENST00000342947.9	TSL:1	c.447A>T	p.Glu149Asp	missense	Exon 4 of 10	ENSP00000339587.3	O60443-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1461150

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726922

African (AFR)

AF:

0.00

AC:

AN:

33476

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52804

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5746

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111928

Other (OTH)

AF:

0.00

AC:

AN:

60384

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.53

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.12

Eigen

Benign

-0.012

Eigen_PC

Benign

-0.12

FATHMM_MKL

Benign

0.29

LIST_S2

Benign

0.84

M_CAP

Benign

0.014

MetaRNN

Uncertain

0.65

MetaSVM

Benign

-0.88

PhyloP100

0.87

PrimateAI

Benign

0.41

PROVEAN

Benign

-1.6

REVEL

Benign

0.076

Sift

Benign

0.062

Sift4G

Benign

0.085

Polyphen

1.0

Vest4

0.33

MutPred

0.45

Gain of loop (P = 0.2045)

MVP

0.52

MPC

0.24

ClinPred

0.89

GERP RS

3.4

PromoterAI

-0.041

Neutral

(source)

Varity_R

0.095

gMVP

0.37

Mutation Taster

=97/3

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over