rs17274530

Variant names:

• chr7-24698996-G-A
• rs17274530
• NM_001127453.2:c.*30C>T

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.*30C>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 0.0513 in 1,480,710 control chromosomes in the GnomAD database, including 2,257 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.038 (154 hom., cov: 32)
  • Exomes 𝑓: 0.053 (2103 hom.)
• Consequence: GSDME NM_001127453.2 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.441

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=-0.91).
• BP6: Variant 7-24698996-G-A is Benign according to our data. Variant chr7-24698996-G-A is described in ClinVar as [Benign]. Clinvar id is 359836.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0554 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GSDME	NM_001127453.2	c.*30C>T		3_prime_UTR_variant	Exon 10 of 10	ENST00000645220.1	NP_001120925.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GSDME	ENST00000645220	c.*30C>T		3_prime_UTR_variant	Exon 10 of 10		NM_001127453.2	ENSP00000494186.1

Frequencies

GnomAD3 genomes AF: 0.0384 AC: 5845 AN: 152196 Hom.: 154 Cov.: 32

Gnomad AFR AF: 0.00919

Gnomad AMI AF: 0.0374

Gnomad AMR AF: 0.0322

Gnomad ASJ AF: 0.0724

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0230

Gnomad FIN AF: 0.0577

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0569

Gnomad OTH AF: 0.0387

GnomAD3 exomes AF: 0.0433 AC: 10256 AN: 236888 Hom.: 254 AF XY: 0.0446 AC XY: 5691 AN XY: 127690

Gnomad AFR exome AF: 0.00784

Gnomad AMR exome AF: 0.0262

Gnomad ASJ exome AF: 0.0713

Gnomad EAS exome AF: 0.000116

Gnomad SAS exome AF: 0.0297

Gnomad FIN exome AF: 0.0612

Gnomad NFE exome AF: 0.0580

Gnomad OTH exome AF: 0.0502

GnomAD4 exome AF: 0.0528 AC: 70136 AN: 1328396 Hom.: 2103 Cov.: 19 AF XY: 0.0521 AC XY: 34759 AN XY: 667028

Gnomad4 AFR exome AF: 0.00723

Gnomad4 AMR exome AF: 0.0270

Gnomad4 ASJ exome AF: 0.0725

Gnomad4 EAS exome AF: 0.000104

Gnomad4 SAS exome AF: 0.0294

Gnomad4 FIN exome AF: 0.0575

Gnomad4 NFE exome AF: 0.0588

Gnomad4 OTH exome AF: 0.0491

GnomAD4 genome AF: 0.0384 AC: 5843 AN: 152314 Hom.: 154 Cov.: 32 AF XY: 0.0373 AC XY: 2781 AN XY: 74472

Gnomad4 AFR AF: 0.00916

Gnomad4 AMR AF: 0.0321

Gnomad4 ASJ AF: 0.0724

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0226

Gnomad4 FIN AF: 0.0577

Gnomad4 NFE AF: 0.0569

Gnomad4 OTH AF: 0.0388

Alfa AF: 0.0537 Hom.: 247

Bravo AF: 0.0357

Asia WGS AF: 0.0130 AC: 46 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

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jun 16, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.12
DANN	Benign	0.47

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: rs17274530; hg19: chr7-24738615;