rs876305

Positions:

• chr7-24719176-T-A
• chr7-24719176-T-C
• chr7-24719176-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001127453.2(GSDME):​c.447A>T​(p.Glu149Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 12/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. E149E) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: GSDME NM_001127453.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.873

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GSDME	NM_001127453.2	c.447A>T	p.Glu149Asp	missense_variant	4/10	ENST00000645220.1	NP_001120925.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GSDME	ENST00000645220.1	c.447A>T	p.Glu149Asp	missense_variant	4/10		NM_001127453.2	ENSP00000494186	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1461150 Hom.: 0 Cov.: 52 AF XY: 0.00 AC XY: 0 AN XY: 726922

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T;T;T;.
Eigen	Benign	-0.012
Eigen_PC	Benign	-0.12
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.84	.;.;T;D
M_CAP	Benign	0.014	T
MetaRNN	Uncertain	0.65	D;D;D;D
MetaSVM	Benign	-0.88	T
MutationTaster	Benign	0.049	P;P;P;P;P
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.6	N;.;N;.
REVEL	Benign	0.076
Sift	Benign	0.062	T;.;T;.
Sift4G	Benign	0.085	T;.;T;.
Polyphen		1.0	D;D;D;.
Vest4		0.33
MutPred		0.45		Gain of loop (P = 0.2045);Gain of loop (P = 0.2045);Gain of loop (P = 0.2045);Gain of loop (P = 0.2045);
MVP		0.52
MPC		0.24
ClinPred		0.89	D
GERP RS		3.4
Varity_R		0.095
gMVP		0.37

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

LitVar

Other links and lift over

dbSNP: rs876305; hg19: chr7-24758795;