7-24698753-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001127453.2(GSDME):c.*273C>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 0.0405 in 483,308 control chromosomes in the GnomAD database, including 1,501 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.070 (910 hom., cov: 32)
  • Exomes 𝑓: 0.027 (591 hom.)
• Consequence: GSDME NM_001127453.2 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.115

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 7-24698753-G-A is Benign according to our data. Variant chr7-24698753-G-A is described in ClinVar as [Benign]. Clinvar id is 359832.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.187 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GSDME	NM_001127453.2	c.*273C>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.*273C>T		3_prime_UTR_variant	10/10		NM_001127453.2	P1

Frequencies

GnomAD3 genomes AF: 0.0695 AC: 10570 AN: 152080 Hom.: 908 Cov.: 32

Gnomad AFR AF: 0.190

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0723

Gnomad ASJ AF: 0.0332

Gnomad EAS AF: 0.189

Gnomad SAS AF: 0.0164

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.00441

Gnomad OTH AF: 0.0532

GnomAD4 exome AF: 0.0271 AC: 8978 AN: 331110 Hom.: 591 Cov.: 0 AF XY: 0.0255 AC XY: 4486 AN XY: 175702

Gnomad4 AFR exome AF: 0.194

Gnomad4 AMR exome AF: 0.0655

Gnomad4 ASJ exome AF: 0.0331

Gnomad4 EAS exome AF: 0.186

Gnomad4 SAS exome AF: 0.0106

Gnomad4 FIN exome AF: 0.000177

Gnomad4 NFE exome AF: 0.00436

Gnomad4 OTH exome AF: 0.0347

GnomAD4 genome AF: 0.0696 AC: 10594 AN: 152198 Hom.: 910 Cov.: 32 AF XY: 0.0696 AC XY: 5182 AN XY: 74422

Gnomad4 AFR AF: 0.190

Gnomad4 AMR AF: 0.0722

Gnomad4 ASJ AF: 0.0332

Gnomad4 EAS AF: 0.189

Gnomad4 SAS AF: 0.0160

Gnomad4 FIN AF: 0.000282

Gnomad4 NFE AF: 0.00441

Gnomad4 OTH AF: 0.0541

Alfa AF: 0.0217 Hom.: 189

Bravo AF: 0.0804

Asia WGS AF: 0.0920 AC: 318 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 17, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
Cadd	Benign	1.7
Dann	Benign	0.50

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: rs17149888; hg19: chr7-24738372;