chr7-24699237-CCAT-C

Variant names:

• chr7-24699237-CCAT-C
• rs374353052
• NM_001127453.2:c.1277_1279delATG

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP3 BP6_Very_Strong BS1 BS2

The NM_001127453.2(GSDME):​c.1277_1279delATG​(p.Asp426del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000295 in 1,613,480 control chromosomes in the GnomAD database, including 6 homozygotes. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. D426D) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00030 (6 hom.)
• Consequence: GSDME NM_001127453.2 disruptive_inframe_deletion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:3
• Conservation: PhyloP100: 1.92
• Publications: 1 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: Benign. The variant received -17 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_001127453.2
• BP6: Variant 7-24699237-CCAT-C is Benign according to our data. Variant chr7-24699237-CCAT-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 163032.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000223 (34/152318) while in subpopulation SAS AF = 0.00332 (16/4824). AF 95% confidence interval is 0.00208. There are 0 homozygotes in GnomAd4. There are 22 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 34 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.1277_1279delATG	p.Asp426del	disruptive_inframe_deletion	Exon 10 of 10	NP_001120925.1	O60443-1
	GSDME	NM_004403.3		c.1277_1279delATG	p.Asp426del	disruptive_inframe_deletion	Exon 10 of 10	NP_004394.1	O60443-1
	GSDME	NM_001127454.2		c.785_787delATG	p.Asp262del	disruptive_inframe_deletion	Exon 9 of 9	NP_001120926.1	O60443-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GSDME	ENST00000645220.1	MANE Select	c.1277_1279delATG	p.Asp426del	disruptive_inframe_deletion	Exon 10 of 10	ENSP00000494186.1	O60443-1
	GSDME	ENST00000342947.9	TSL:1	c.1277_1279delATG	p.Asp426del	disruptive_inframe_deletion	Exon 10 of 10	ENSP00000339587.3	O60443-1
	GSDME	ENST00000419307.6	TSL:1	c.785_787delATG	p.Asp262del	disruptive_inframe_deletion	Exon 9 of 9	ENSP00000401332.1	O60443-3

Frequencies

GnomAD3 genomes AF: 0.000223 AC: 34 AN: 152200 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000290

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000962

Gnomad SAS AF: 0.00331

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000684 AC: 172 AN: 251364 AF XY: 0.000802

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000489

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.000302 AC: 442 AN: 1461162 Hom.: 6 AF XY: 0.000409 AC XY: 297 AN XY: 726964

African (AFR) AF: 0.000179 AC: 6 AN: 33466

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.000403 AC: 16 AN: 39694

South Asian (SAS) AF: 0.00417 AC: 360 AN: 86228

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

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

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1111376

Other (OTH) AF: 0.000911 AC: 55 AN: 60370

GnomAD4 genome AF: 0.000223 AC: 34 AN: 152318 Hom.: 0 Cov.: 32 AF XY: 0.000295 AC XY: 22 AN XY: 74480

African (AFR) AF: 0.000289 AC: 12 AN: 41566

American (AMR) AF: 0.00 AC: 0 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000964 AC: 5 AN: 5188

South Asian (SAS) AF: 0.00332 AC: 16 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.0000982

Asia WGS AF: 0.00606 AC: 21 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	Autosomal dominant nonsyndromic hearing loss 5 (1)
-	-	1	GSDME-related disorder (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.9
Mutation Taster		=74/26	disease causing (ClinVar)

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: rs374353052; hg19: chr7-24738856;