7-24749655-CTTTT-CTTTTT

Variant names:

• chr7-24749655-C-CT
• rs758488919
• NM_001127453.2:c.119dupA

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 8P and 9B. PVS1 BP6 BS1 BS2

The NM_001127453.2(GSDME):​c.119dupA​(p.Lys41GlufsTer113) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00075 in 1,613,944 control chromosomes in the GnomAD database, including 16 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.00083 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00074 (14 hom.)
• Consequence: GSDME NM_001127453.2 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 0.526
• Publications: 2 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):

• nonsyndromic genetic hearing loss

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

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• autosomal dominant nonsyndromic hearing loss

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• BP6: Variant 7-24749655-C-CT is Benign according to our data. Variant chr7-24749655-C-CT is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 228555.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000835 (127/152160) while in subpopulation NFE AF = 0.000235 (16/68022). AF 95% confidence interval is 0.000147. There are 2 homozygotes in GnomAd4. There are 48 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 127 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001127453.2. 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.119dupA	p.Lys41GlufsTer113	frameshift	Exon 2 of 10	NP_001120925.1	O60443-1
	GSDME	NM_004403.3		c.119dupA	p.Lys41GlufsTer113	frameshift	Exon 2 of 10	NP_004394.1	O60443-1
	GSDME	NM_001127454.2		c.-281-4902dupA		intron	N/A	NP_001120926.1	O60443-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GSDME	ENST00000645220.1	MANE Select	c.119dupA	p.Lys41GlufsTer113	frameshift	Exon 2 of 10	ENSP00000494186.1	O60443-1
	GSDME	ENST00000342947.9	TSL:1	c.119dupA	p.Lys41GlufsTer113	frameshift	Exon 2 of 10	ENSP00000339587.3	O60443-1
	GSDME	ENST00000419307.6	TSL:1	c.-281-4902dupA		intron	N/A	ENSP00000401332.1	O60443-3

Frequencies

GnomAD3 genomes AF: 0.000835 AC: 127 AN: 152160 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.0300

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.00152 AC: 381 AN: 251436 AF XY: 0.00130

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0320

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000360

Gnomad OTH exome AF: 0.00261

GnomAD4 exome AF: 0.000742 AC: 1084 AN: 1461784 Hom.: 14 Cov.: 33 AF XY: 0.000712 AC XY: 518 AN XY: 727200

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0297 AC: 775 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53388

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000159 AC: 177 AN: 1111938

Other (OTH) AF: 0.00217 AC: 131 AN: 60396

GnomAD4 genome AF: 0.000835 AC: 127 AN: 152160 Hom.: 2 Cov.: 32 AF XY: 0.000646 AC XY: 48 AN XY: 74332

African (AFR) AF: 0.000121 AC: 5 AN: 41452

American (AMR) AF: 0.00 AC: 0 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.0300 AC: 104 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000235 AC: 16 AN: 68022

Other (OTH) AF: 0.000956 AC: 2 AN: 2092

Alfa AF: 0.00417 Hom.: 2

Bravo AF: 0.000812

EpiCase AF: 0.000436

EpiControl AF: 0.000415

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	GSDME-related disorder (1)
-	-	1	Nonsyndromic genetic hearing loss (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.53
Mutation Taster		=172/28	disease causing (fs/PTC)

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

Other links and lift over

dbSNP: rs758488919; hg19: chr7-24789274;