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):

• 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

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).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GSDME	NM_001127453.2	c.1213G>A	p.Gly405Ser	missense_variant	Exon 9 of 10	ENST00000645220.1	NP_001120925.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GSDME	ENST00000645220.1	c.1213G>A	p.Gly405Ser	missense_variant	Exon 9 of 10		NM_001127453.2	ENSP00000494186.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 06, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant classified as Uncertain Significance - Favor Benign. The p.Gly405Ser var iant in DFNA5 has not been previously reported in individuals with hearing loss and was absent from large population studies. The glycine (Gly) at position 405 is not conserved in mammals or evolutionary distant species, with two mammals ( elephant and manatee) having a serine (Ser) at this position, supporting that a change at this position may be tolerated. Additional computational prediction to ols suggest that the p.Gly405Ser variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. Pathogenic var iants in DFNA5 reported to date result in skipping of exon 8. This variant is no t predicted to impact splicing; however, functional studies are needed to comple tely rule out an impact to splicing. In summary, while the clinical significance of the p.Gly405Ser variant is uncertain, these data suggest that it is more lik ely to be benign. -

Computational scores

Source: dbNSFP v4.3

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;T;.;.;T;.
Eigen	Benign	-0.046
Eigen_PC	Benign	0.053
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.74	.;.;.;T;T;T
M_CAP	Benign	0.0095	T
MetaRNN	Benign	0.33	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
PhyloP100		0.77
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.3	N;.;D;D;N;D
REVEL	Benign	0.11
Sift	Benign	0.063	T;.;T;T;T;D
Sift4G	Benign	0.36	T;.;T;T;T;D
Polyphen		0.32	B;B;.;.;B;.
Vest4		0.23
MutPred		0.65		Loss of ubiquitination at K409 (P = 0.0768);Loss of ubiquitination at K409 (P = 0.0768);.;.;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;