rs727505273

Variant names:

• chr7-24706388-GGAA-G
• rs727505273
• NM_001127453.2:c.991-15_991-13delTTC

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 12P and 4B. PS3 PP5_Very_Strong BS2

The NM_001127453.2(GSDME):​c.991-15_991-13delTTC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,458,406 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV001768211: Published functional studies demonstrate adjacent exon 8 skipping and describe a hypothesized dominant-negative mechanism (PMID:14559215)" and additional evidence is available in ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: GSDME NM_001127453.2 intron
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:12
• Conservation: PhyloP100: 0.527
• 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):

• 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_pathogenic. The variant received 8 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV001768211: Published functional studies demonstrate adjacent exon 8 skipping and describe a hypothesized dominant-negative mechanism (PMID: 14559215); SCV004294458: Studies have shown that this variant results in skipping of exon 8 and introduces a new termination codon (PMID: 14559215).; SCV002059892: Analysis of patient-derived RNA indicates that DFNA5/GSDME c.991-15_991-13delTTC weakens exon 8 splice acceptor, leading to loss of exon 8 in message and stop at codon 372 (Abu Rayyan 2020).; SCV005049566: Experimental data suggest that the variant leads to skipping of exon 8 and thus to a non-functional protein (PMID: 14559215).; SCV005416637: "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product."
• PP5: Variant 7-24706388-GGAA-G is Pathogenic according to our data. Variant chr7-24706388-GGAA-G is described in ClinVar as Pathogenic. ClinVar VariationId is 179997.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAdExome4 at 6 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.991-15_991-13delTTC		intron	N/A	NP_001120925.1	O60443-1
	GSDME	NM_004403.3		c.991-15_991-13delTTC		intron	N/A	NP_004394.1	O60443-1
	GSDME	NM_001127454.2		c.499-15_499-13delTTC		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.991-15_991-13delTTC		intron	N/A	ENSP00000494186.1	O60443-1
	GSDME	ENST00000342947.9	TSL:1	c.991-15_991-13delTTC		intron	N/A	ENSP00000339587.3	O60443-1
	GSDME	ENST00000419307.6	TSL:1	c.499-15_499-13delTTC		intron	N/A	ENSP00000401332.1	O60443-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000411 AC: 1 AN: 243602 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000918

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1458406 Hom.: 0 AF XY: 0.00000414 AC XY: 3 AN XY: 725428

African (AFR) AF: 0.0000300 AC: 1 AN: 33368

American (AMR) AF: 0.00 AC: 0 AN: 44564

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26088

East Asian (EAS) AF: 0.00 AC: 0 AN: 39562

South Asian (SAS) AF: 0.00 AC: 0 AN: 85852

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53290

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4320

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111218

Other (OTH) AF: 0.0000166 AC: 1 AN: 60144

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
6	-	-	Autosomal dominant nonsyndromic hearing loss 5 (6)
4	-	-	not provided (4)
1	-	-	Monogenic hearing loss (1)
1	-	-	Rare genetic deafness (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.53
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs727505273; hg19: chr7-24746007;