7-24702804-C-T

Variant names:

• chr7-24702804-C-T
• rs566450742
• NM_001127453.2:c.1213G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001127453.2(GSDME):​c.1213G>A​(p.Gly405Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: GSDME NM_001127453.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.769
• Publications: 0 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3313108).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GSDME	NM_001127453.2	MANE Select	c.1213G>A	p.Gly405Ser	missense	Exon 9 of 10	NP_001120925.1	O60443-1
	GSDME	NM_004403.3		c.1213G>A	p.Gly405Ser	missense	Exon 9 of 10	NP_004394.1	O60443-1
	GSDME	NM_001127454.2		c.721G>A	p.Gly241Ser	missense	Exon 8 of 9	NP_001120926.1	O60443-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GSDME	ENST00000645220.1	MANE Select	c.1213G>A	p.Gly405Ser	missense	Exon 9 of 10	ENSP00000494186.1	O60443-1
	GSDME	ENST00000342947.9	TSL:1	c.1213G>A	p.Gly405Ser	missense	Exon 9 of 10	ENSP00000339587.3	O60443-1
	GSDME	ENST00000419307.6	TSL:1	c.721G>A	p.Gly241Ser	missense	Exon 8 of 9	ENSP00000401332.1	O60443-3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.054	T
Eigen	Benign	-0.046
Eigen_PC	Benign	0.053
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.0095	T
MetaRNN	Benign	0.33	T
MetaSVM	Benign	-1.0	T
PhyloP100		0.77
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.11
Sift	Benign	0.063	T
Sift4G	Benign	0.36	T
Polyphen		0.32	B
Vest4		0.23
MutPred		0.65		Loss of ubiquitination at K409 (P = 0.0768)
MVP		0.26
MPC		0.094
ClinPred		0.62	D
GERP RS		4.9
Varity_R		0.046
gMVP		0.28
Mutation Taster		=87/13	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs566450742; hg19: chr7-24742423;