rs1554325967

chr7-24717295-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM2 PP3_Moderate BP6_Moderate

The NM_001127453.2(GSDME):c.656A>G(p.Tyr219Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,672 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: GSDME NM_001127453.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.990

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
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.882
• BP6: Variant 7-24717295-T-C is Benign according to our data. Variant chr7-24717295-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 504951.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GSDME	NM_001127453.2	c.656A>G	p.Tyr219Cys	missense_variant	5/10	ENST00000645220.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GSDME	ENST00000645220.1	c.656A>G	p.Tyr219Cys	missense_variant	5/10		NM_001127453.2	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461672 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727126

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 02, 2016

p.Tyr219Cys in exon 5 of DFNA5: This variant is not expected to have clinical si gnificance due to a lack of conservation across species, including mammals. Of n ote, 5 mammals have a cysteine (Cys) at this position despite high nearby amino acid conservation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
Cadd	Benign	15
Dann	Uncertain	0.99
DEOGEN2	Benign	0.35	T;T;.;.;T;.
Eigen	Benign	-0.049
Eigen_PC	Benign	0.030
FATHMM_MKL	Benign	0.49	N
M_CAP	Benign	0.017	T
MetaRNN	Pathogenic	0.88	D;D;D;D;D;D
MetaSVM	Benign	-0.87	T
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Benign	0.46	T
PROVEAN	Pathogenic	-5.6	D;.;D;D;D;.
REVEL	Uncertain	0.30
Sift	Uncertain	0.021	D;.;D;D;D;.
Sift4G	Benign	0.069	T;.;T;T;T;.
Polyphen		0.13	B;B;.;.;B;.
Vest4		0.47
MutPred		0.86		Gain of sheet (P = 0.0266);Gain of sheet (P = 0.0266);.;.;Gain of sheet (P = 0.0266);Gain of sheet (P = 0.0266);
MVP		0.68
MPC		0.065
ClinPred		0.90	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.29
gMVP		0.87

Splicing

Name	Calibrated prediction	Score	Prediction
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

LitVar

Other links and lift over

dbSNP: rs1554325967; hg19: chr7-24756914;