7-24698499-G-A

Variant names:

• chr7-24698499-G-A
• rs6957782
• NM_001127453.2:c.*527C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001127453.2(GSDME):​c.*527C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0632 in 188,320 control chromosomes in the GnomAD database, including 502 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.070 (466 hom., cov: 32)
  • Exomes 𝑓: 0.035 (36 hom.)
• Consequence: GSDME NM_001127453.2 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.477
• Publications: 5 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 7-24698499-G-A is Benign according to our data. Variant chr7-24698499-G-A is described in ClinVar as Benign. ClinVar VariationId is 359822.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.116 is higher than 0.05.

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.*527C>T		3_prime_UTR	Exon 10 of 10	NP_001120925.1	O60443-1
	GSDME	NM_004403.3		c.*527C>T		3_prime_UTR	Exon 10 of 10	NP_004394.1	O60443-1
	GSDME	NM_001127454.2		c.*527C>T		3_prime_UTR	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.*527C>T		3_prime_UTR	Exon 10 of 10	ENSP00000494186.1	O60443-1
	GSDME	ENST00000342947.9	TSL:1	c.*527C>T		3_prime_UTR	Exon 10 of 10	ENSP00000339587.3	O60443-1
	GSDME	ENST00000419307.6	TSL:1	c.*527C>T		3_prime_UTR	Exon 9 of 9	ENSP00000401332.1	O60443-3

Frequencies

GnomAD3 genomes AF: 0.0700 AC: 10609 AN: 151464 Hom.: 465 Cov.: 32

Gnomad AFR AF: 0.119

Gnomad AMI AF: 0.0373

Gnomad AMR AF: 0.0433

Gnomad ASJ AF: 0.0727

Gnomad EAS AF: 0.000196

Gnomad SAS AF: 0.0236

Gnomad FIN AF: 0.0576

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0576

Gnomad OTH AF: 0.0623

GnomAD4 exome AF: 0.0350 AC: 1287 AN: 36736 Hom.: 36 Cov.: 0 AF XY: 0.0348 AC XY: 649 AN XY: 18652

African (AFR) AF: 0.0671 AC: 29 AN: 432

American (AMR) AF: 0.0381 AC: 123 AN: 3228

Ashkenazi Jewish (ASJ) AF: 0.0531 AC: 38 AN: 716

East Asian (EAS) AF: 0.00 AC: 0 AN: 1902

South Asian (SAS) AF: 0.0191 AC: 77 AN: 4028

European-Finnish (FIN) AF: 0.0264 AC: 42 AN: 1588

Middle Eastern (MID) AF: 0.0333 AC: 5 AN: 150

European-Non Finnish (NFE) AF: 0.0398 AC: 903 AN: 22668

Other (OTH) AF: 0.0346 AC: 70 AN: 2024

GnomAD4 genome AF: 0.0701 AC: 10619 AN: 151584 Hom.: 466 Cov.: 32 AF XY: 0.0678 AC XY: 5020 AN XY: 74090

African (AFR) AF: 0.119 AC: 4895 AN: 41054

American (AMR) AF: 0.0432 AC: 657 AN: 15224

Ashkenazi Jewish (ASJ) AF: 0.0727 AC: 252 AN: 3468

East Asian (EAS) AF: 0.000196 AC: 1 AN: 5096

South Asian (SAS) AF: 0.0232 AC: 112 AN: 4832

European-Finnish (FIN) AF: 0.0576 AC: 611 AN: 10604

Middle Eastern (MID) AF: 0.0374 AC: 11 AN: 294

European-Non Finnish (NFE) AF: 0.0576 AC: 3915 AN: 67990

Other (OTH) AF: 0.0621 AC: 131 AN: 2110

Alfa AF: 0.0632 Hom.: 442

Bravo AF: 0.0724

Asia WGS AF: 0.0210 AC: 72 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Autosomal dominant nonsyndromic hearing loss 5 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.33
DANN	Benign	0.36
PhyloP100		-0.48
Mutation Taster		=100/0	polymorphism (auto)

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: rs6957782; hg19: chr7-24738118; COSMIC: COSV105032350; COSMIC: COSV105032350;