7-24698499-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001127453.2(GSDME):c.*527C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0632 in 188,320 control chromosomes in the GnomAD database, including 502 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.070 (466 hom., cov: 32)
  • Exomes 𝑓: 0.035 (36 hom.)
• Consequence: GSDME NM_001127453.2 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.477

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 7-24698499-G-A is Benign according to our data. Variant chr7-24698499-G-A is described in ClinVar as [Benign]. Clinvar id is 359822.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.116 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GSDME	NM_001127453.2	c.*527C>T		3_prime_UTR_variant	10/10	ENST00000645220.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GSDME	ENST00000645220.1	c.*527C>T		3_prime_UTR_variant	10/10		NM_001127453.2	P1

Frequencies

GnomAD3 genomes AF: 0.0700 AC: 10609 AN: 151464 Hom.: 465 Cov.: 32

Gnomad AFR AF: 0.119

Gnomad AMI AF: 0.0373

Gnomad AMR AF: 0.0433

Gnomad ASJ AF: 0.0727

Gnomad EAS AF: 0.000196

Gnomad SAS AF: 0.0236

Gnomad FIN AF: 0.0576

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0576

Gnomad OTH AF: 0.0623

GnomAD4 exome AF: 0.0350 AC: 1287 AN: 36736 Hom.: 36 Cov.: 0 AF XY: 0.0348 AC XY: 649 AN XY: 18652

Gnomad4 AFR exome AF: 0.0671

Gnomad4 AMR exome AF: 0.0381

Gnomad4 ASJ exome AF: 0.0531

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0191

Gnomad4 FIN exome AF: 0.0264

Gnomad4 NFE exome AF: 0.0398

Gnomad4 OTH exome AF: 0.0346

GnomAD4 genome AF: 0.0701 AC: 10619 AN: 151584 Hom.: 466 Cov.: 32 AF XY: 0.0678 AC XY: 5020 AN XY: 74090

Gnomad4 AFR AF: 0.119

Gnomad4 AMR AF: 0.0432

Gnomad4 ASJ AF: 0.0727

Gnomad4 EAS AF: 0.000196

Gnomad4 SAS AF: 0.0232

Gnomad4 FIN AF: 0.0576

Gnomad4 NFE AF: 0.0576

Gnomad4 OTH AF: 0.0621

Alfa AF: 0.0614 Hom.: 312

Bravo AF: 0.0724

Asia WGS AF: 0.0210 AC: 72 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal dominant nonsyndromic hearing loss 5 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
Cadd	Benign	0.33
Dann	Benign	0.36

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: rs6957782; hg19: chr7-24738118; COSMIC: COSV105032350; COSMIC: COSV105032350;