rs727505273

Positions:

• chr7-24706388-GGAA-G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PP5_Very_Strong

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 (★★).

• 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:11
• Conservation: PhyloP100: 0.527

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 Likely_pathogenic. Variant got 8 ACMG points.

• PP5: Variant 7-24706388-GGAA-G is Pathogenic according to our data. Variant chr7-24706388-GGAA-G is described in ClinVar as [Pathogenic]. Clinvar id is 179997.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-24706388-GGAA-G is described in Lovd as [Likely_pathogenic]. Variant chr7-24706388-GGAA-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GSDME	NM_001127453.2	c.991-15_991-13delTTC		intron_variant		ENST00000645220.1	NP_001120925.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GSDME	ENST00000645220.1	c.991-15_991-13delTTC		intron_variant			NM_001127453.2	ENSP00000494186.1
GSDME	ENST00000342947.9	c.991-15_991-13delTTC		intron_variant		1		ENSP00000339587.3
GSDME	ENST00000419307.6	c.499-15_499-13delTTC		intron_variant		1		ENSP00000401332.1
GSDME	ENST00000409970.6	c.499-15_499-13delTTC		intron_variant		5		ENSP00000387119.1

Frequencies

GnomAD3 genomes Cov.: 32

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

Gnomad4 AFR exome AF: 0.0000300

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal dominant nonsyndromic hearing loss 5 Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 02, 2022	- -
Pathogenic, criteria provided, single submitter	research	King Laboratory, University of Washington	Aug 01, 2020	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). The variant is heterozygous in 5 Palestinian children with progressive hearing loss, with average age at onset of 17 years. It is absent from 1300 Palestinian controls and from gnomAD v2.1.1. -
Pathogenic, criteria provided, single submitter	clinical testing	Juno Genomics, Hangzhou Juno Genomics, Inc	-	PM2_Supporting+PP1_Strong+PS4_Moderate+PS3 -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostics Centre, Carl Von Ossietzky University Oldenburg	Oct 24, 2023	The GSDME:c.991-15_991-13delTTC splice variant is located 13 nucleotides upstream of exon 7 of the GSDME gene. This variant is classified as very rare in the overall population (allele frequency in gnomAD, v4.1.0= 0.000004114). The variant has been consistently classified as Pathogenic in nine entries in ClinVar (ClinVarID: 179997). The variant has been reported in several affected individuals with sensorineural with hearing loss and to co-segregate with the disease (PMID: 24506266, 19911014, 14559215). Experimental data suggest that the variant leads to skipping of exon 8 and thus to a non-functional protein (PMID: 14559215). In summary, this variant is classified as Pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2010	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Mar 22, 2022	The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 24506266, 19911014, 14559215) and reported to co-segregate with the disease in at least 7 similarly affected relatives/individuals in at least two unrelated families (PMID: 19911014, 14559215). The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000179997, PMID:14559215). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0000041). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 01, 2023	This sequence change falls in intron 7 of the DFNA5 gene. It does not directly change the encoded amino acid sequence of the DFNA5 protein. RNA analysis indicates that this variant induces altered splicing and likely disrupts the C-terminus of the protein. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has been observed in individuals with non-syndromic deafness (PMID: 14559215, 29266521). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 179997). Studies have shown that this variant results in skipping of exon 8 and introduces a new termination codon (PMID: 14559215). However the mRNA is not expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Sep 15, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 11, 2022	Published functional studies demonstrate adjacent exon 8 skipping and describe a hypothesized dominant-negative mechanism (Yu et al., 2003).; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis, which includes splice predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24506266, 14676472, 9771715, 17868390, 14559215, 29266521, 29849037, 32486382, 32747562, 19911014) -

Rare genetic deafness Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Oct 03, 2014

c.991-21TTC[2] (DFNA5; NM_004403.2; Chr7g.24746008_24746010delGAA; GRCh37): The c.991-21TTC[2] variant in DFNA5 has been reported in 4 Asian individuals with no n-syndromic sensorineural hearing loss, segregated with disease in 27 affected r elatives from 3 families and was absent in 440 Asian control chromosomes (Yu 200 3, Park 2010, Nisho 2014). It has also been previously identified by our laborat ory in one individual with hearing loss. This variant is a deletion of one unit of a trinucleotide (TTC) repeat sequence normally present as a triplicate (3 rep eat units), resulting in two copies of the TTC repeat. This variant is located i n the 3' splice region and has been shown to cause aberrant splicing, by skippin g of exon 8 (Yu 2003), which is predicted to lead to an abnormal or absent prote in. Several other variants in DFNA5 that have been reported to cause hearing los s are located in introns 7 or 8 and are expected to cause exon 8 skipping (Bisch off 2004, Van Laer 2005, Cheng 2007). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant hearing loss based on the pr evious reports in affected individuals, segregations, and absence in controls. -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs727505273; hg19: chr7-24746007;