rs10486429

Variant names:

• chr7-24703859-G-A
• rs10486429
• NM_001127453.2:c.1184-1026C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004403.3(GSDME):​c.1184-1026C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0385 in 152,336 control chromosomes in the GnomAD database, including 158 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.038 (158 hom., cov: 32)
  • Exomes 𝑓: 0.056 (0 hom.)
• Consequence: GSDME NM_004403.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.715
• Publications: 4 publications found

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]

GSDME Gene-Disease associations (from GenCC):

• autosomal dominant nonsyndromic hearing loss

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• autosomal dominant nonsyndromic hearing loss 5

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0555 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004403.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GSDME	NM_001127453.2	MANE Select	c.1184-1026C>T		intron	N/A	NP_001120925.1
	GSDME	NM_004403.3		c.1184-1026C>T		intron	N/A	NP_004394.1
	GSDME	NM_001127454.2		c.692-1026C>T		intron	N/A	NP_001120926.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GSDME	ENST00000645220.1	MANE Select	c.1184-1026C>T		intron	N/A	ENSP00000494186.1
	GSDME	ENST00000342947.9	TSL:1	c.1184-1026C>T		intron	N/A	ENSP00000339587.3
	GSDME	ENST00000419307.6	TSL:1	c.692-1026C>T		intron	N/A	ENSP00000401332.1

Frequencies

GnomAD3 genomes AF: 0.0385 AC: 5861 AN: 152182 Hom.: 157 Cov.: 32

Gnomad AFR AF: 0.00951

Gnomad AMI AF: 0.0373

Gnomad AMR AF: 0.0322

Gnomad ASJ AF: 0.0726

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0226

Gnomad FIN AF: 0.0577

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0570

Gnomad OTH AF: 0.0397

GnomAD4 exome AF: 0.0556 AC: 2 AN: 36 Hom.: 0 Cov.: 0 AF XY: 0.0667 AC XY: 2 AN XY: 30

African (AFR) AF: 0.00 AC: 0 AN: 2

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.0625 AC: 2 AN: 32

Other (OTH) AF: 0.00 AC: 0 AN: 2

GnomAD4 genome AF: 0.0385 AC: 5862 AN: 152300 Hom.: 158 Cov.: 32 AF XY: 0.0374 AC XY: 2786 AN XY: 74464

African (AFR) AF: 0.00955 AC: 397 AN: 41570

American (AMR) AF: 0.0321 AC: 491 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0726 AC: 252 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5186

South Asian (SAS) AF: 0.0222 AC: 107 AN: 4822

European-Finnish (FIN) AF: 0.0577 AC: 612 AN: 10612

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0570 AC: 3874 AN: 68016

Other (OTH) AF: 0.0397 AC: 84 AN: 2114

Alfa AF: 0.0538 Hom.: 117

Bravo AF: 0.0359

Asia WGS AF: 0.0130 AC: 46 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.98
DANN	Benign	0.35
PhyloP100		0.71
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs10486429; hg19: chr7-24743478;