rs55735863

Positions:

• chr7-24708260-A-G

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.863-6T>C variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0515 in 1,613,916 control chromosomes in the GnomAD database, including 2,473 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.039 (157 hom., cov: 32)
  • Exomes 𝑓: 0.053 (2316 hom.)
• Consequence: GSDME NM_001127453.2 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00002882
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.142

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=-0.83).
• BP6: Variant 7-24708260-A-G is Benign according to our data. Variant chr7-24708260-A-G is described in ClinVar as [Benign]. Clinvar id is 44848.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0555 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GSDME	NM_001127453.2	c.863-6T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000645220.1	NP_001120925.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GSDME	ENST00000645220.1	c.863-6T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			NM_001127453.2	ENSP00000494186	P1

Frequencies

GnomAD3 genomes AF: 0.0386 AC: 5869 AN: 152196 Hom.: 156 Cov.: 32

Gnomad AFR AF: 0.00955

Gnomad AMI AF: 0.0373

Gnomad AMR AF: 0.0321

Gnomad ASJ AF: 0.0729

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0228

Gnomad FIN AF: 0.0576

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0570

Gnomad OTH AF: 0.0398

GnomAD3 exomes AF: 0.0435 AC: 10929 AN: 251222 Hom.: 289 AF XY: 0.0448 AC XY: 6079 AN XY: 135796

Gnomad AFR exome AF: 0.00825

Gnomad AMR exome AF: 0.0263

Gnomad ASJ exome AF: 0.0714

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.0294

Gnomad FIN exome AF: 0.0615

Gnomad NFE exome AF: 0.0583

Gnomad OTH exome AF: 0.0507

GnomAD4 exome AF: 0.0528 AC: 77230 AN: 1461602 Hom.: 2316 Cov.: 31 AF XY: 0.0521 AC XY: 37892 AN XY: 727106

Gnomad4 AFR exome AF: 0.00750

Gnomad4 AMR exome AF: 0.0275

Gnomad4 ASJ exome AF: 0.0728

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.0292

Gnomad4 FIN exome AF: 0.0578

Gnomad4 NFE exome AF: 0.0585

Gnomad4 OTH exome AF: 0.0492

GnomAD4 genome AF: 0.0385 AC: 5870 AN: 152314 Hom.: 157 Cov.: 32 AF XY: 0.0374 AC XY: 2789 AN XY: 74482

Gnomad4 AFR AF: 0.00960

Gnomad4 AMR AF: 0.0320

Gnomad4 ASJ AF: 0.0729

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0224

Gnomad4 FIN AF: 0.0576

Gnomad4 NFE AF: 0.0570

Gnomad4 OTH AF: 0.0398

Alfa AF: 0.0524 Hom.: 98

Bravo AF: 0.0359

Asia WGS AF: 0.0130 AC: 46 AN: 3478

EpiCase AF: 0.0622

EpiControl AF: 0.0569

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	863-6T>C in Intron 06 of DFNA5: This variant is not expected to have clinical si gnificance because it has been identified in 5.4% (380/7020) of European America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs55735863). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 03, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Autosomal dominant nonsyndromic hearing loss 5 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.75
DANN	Benign	0.48

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000029
dbscSNV1_RF	Benign	0.0
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: rs55735863; hg19: chr7-24747879;