NM_001127453.2:c.*30C>T

Variant names:

• chr7-24698996-G-A
• rs17274530
• NM_001127453.2:c.*30C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001127453.2(GSDME):​c.*30C>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 0.0513 in 1,480,710 control chromosomes in the GnomAD database, including 2,257 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.038 (154 hom., cov: 32)
  • Exomes 𝑓: 0.053 (2103 hom.)
• Consequence: GSDME NM_001127453.2 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.441
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 7-24698996-G-A is Benign according to our data. Variant chr7-24698996-G-A is described in ClinVar as Benign. ClinVar VariationId is 359836.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0554 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.*30C>T		3_prime_UTR	Exon 10 of 10	NP_001120925.1	O60443-1
	GSDME	NM_004403.3		c.*30C>T		3_prime_UTR	Exon 10 of 10	NP_004394.1	O60443-1
	GSDME	NM_001127454.2		c.*30C>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.*30C>T		3_prime_UTR	Exon 10 of 10	ENSP00000494186.1	O60443-1
	GSDME	ENST00000342947.9	TSL:1	c.*30C>T		3_prime_UTR	Exon 10 of 10	ENSP00000339587.3	O60443-1
	GSDME	ENST00000419307.6	TSL:1	c.*30C>T		3_prime_UTR	Exon 9 of 9	ENSP00000401332.1	O60443-3

Frequencies

GnomAD3 genomes AF: 0.0384 AC: 5845 AN: 152196 Hom.: 154 Cov.: 32

Gnomad AFR AF: 0.00919

Gnomad AMI AF: 0.0374

Gnomad AMR AF: 0.0322

Gnomad ASJ AF: 0.0724

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0230

Gnomad FIN AF: 0.0577

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0569

Gnomad OTH AF: 0.0387

GnomAD2 exomes AF: 0.0433 AC: 10256 AN: 236888 AF XY: 0.0446

Gnomad AFR exome AF: 0.00784

Gnomad AMR exome AF: 0.0262

Gnomad ASJ exome AF: 0.0713

Gnomad EAS exome AF: 0.000116

Gnomad FIN exome AF: 0.0612

Gnomad NFE exome AF: 0.0580

Gnomad OTH exome AF: 0.0502

GnomAD4 exome AF: 0.0528 AC: 70136 AN: 1328396 Hom.: 2103 Cov.: 19 AF XY: 0.0521 AC XY: 34759 AN XY: 667028

African (AFR) AF: 0.00723 AC: 221 AN: 30586

American (AMR) AF: 0.0270 AC: 1181 AN: 43794

Ashkenazi Jewish (ASJ) AF: 0.0725 AC: 1826 AN: 25200

East Asian (EAS) AF: 0.000104 AC: 4 AN: 38444

South Asian (SAS) AF: 0.0294 AC: 2411 AN: 82048

European-Finnish (FIN) AF: 0.0575 AC: 3044 AN: 52962

Middle Eastern (MID) AF: 0.0455 AC: 253 AN: 5558

European-Non Finnish (NFE) AF: 0.0588 AC: 58454 AN: 993924

Other (OTH) AF: 0.0491 AC: 2742 AN: 55880

GnomAD4 genome AF: 0.0384 AC: 5843 AN: 152314 Hom.: 154 Cov.: 32 AF XY: 0.0373 AC XY: 2781 AN XY: 74472

African (AFR) AF: 0.00916 AC: 381 AN: 41582

American (AMR) AF: 0.0321 AC: 491 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0724 AC: 251 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5188

South Asian (SAS) AF: 0.0226 AC: 109 AN: 4824

European-Finnish (FIN) AF: 0.0577 AC: 612 AN: 10612

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0569 AC: 3872 AN: 68018

Other (OTH) AF: 0.0388 AC: 82 AN: 2114

Alfa AF: 0.0518 Hom.: 313

Bravo AF: 0.0357

Asia WGS AF: 0.0130 AC: 46 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.12
DANN	Benign	0.47
PhyloP100		-0.44
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: rs17274530; hg19: chr7-24738615; COSMIC: COSV107295807; COSMIC: COSV107295807;