rs11970787

chr7-24717389-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001127453.2(GSDME):c.577-15C>T variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00189 in 1,613,978 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0063 (9 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (10 hom.)
• Consequence: GSDME NM_001127453.2 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.20

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 7-24717389-G-A is Benign according to our data. Variant chr7-24717389-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 44846.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00626 (952/152194) while in subpopulation AFR AF= 0.018 (748/41516). AF 95% confidence interval is 0.0169. There are 9 homozygotes in gnomad4. There are 455 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 950 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GSDME	NM_001127453.2	c.577-15C>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000645220.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GSDME	ENST00000645220.1	c.577-15C>T		splice_polypyrimidine_tract_variant, intron_variant			NM_001127453.2	P1

Frequencies

GnomAD3 genomes AF: 0.00625 AC: 950 AN: 152076 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.0180

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00216

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0102

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000706

Gnomad OTH AF: 0.00669

GnomAD3 exomes AF: 0.00299 AC: 750 AN: 250854 Hom.: 10 AF XY: 0.00246 AC XY: 333 AN XY: 135572

Gnomad AFR exome AF: 0.0193

Gnomad AMR exome AF: 0.00197

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.0108

Gnomad NFE exome AF: 0.000927

Gnomad OTH exome AF: 0.00441

GnomAD4 exome AF: 0.00143 AC: 2095 AN: 1461784 Hom.: 10 Cov.: 33 AF XY: 0.00130 AC XY: 942 AN XY: 727200

Gnomad4 AFR exome AF: 0.0211

Gnomad4 AMR exome AF: 0.00206

Gnomad4 ASJ exome AF: 0.0000765

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.00961

Gnomad4 NFE exome AF: 0.000522

Gnomad4 OTH exome AF: 0.00280

GnomAD4 genome AF: 0.00626 AC: 952 AN: 152194 Hom.: 9 Cov.: 32 AF XY: 0.00612 AC XY: 455 AN XY: 74404

Gnomad4 AFR AF: 0.0180

Gnomad4 AMR AF: 0.00216

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.0102

Gnomad4 NFE AF: 0.000706

Gnomad4 OTH AF: 0.00662

Alfa AF: 0.00291 Hom.: 2

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 21, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 17, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 07, 2012

577-15C>T in Intron 04 of DFNA5: This variant is not expected to have clinical s ignificance because it has been identified in 2.2% (83/3738) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs11970787). -

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	-0.91
Cadd	Benign	0.039
Dann	Benign	0.57

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: rs11970787; hg19: chr7-24757008;