chr7-24719134-C-T

Variant names:

• chr7-24719134-C-T
• rs754555
• NM_001127453.2:c.489G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001127453.2(GSDME):​c.489G>A​(p.Thr163Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.174 in 1,613,482 control chromosomes in the GnomAD database, including 27,809 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (2874 hom., cov: 33)
  • Exomes 𝑓: 0.17 (24935 hom.)
• Consequence: GSDME NM_001127453.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.510
• Publications: 35 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 7-24719134-C-T is Benign according to our data. Variant chr7-24719134-C-T is described in ClinVar as Benign. ClinVar VariationId is 44845.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.51 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.445 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.489G>A	p.Thr163Thr	synonymous	Exon 4 of 10	NP_001120925.1	O60443-1
	GSDME	NM_004403.3		c.489G>A	p.Thr163Thr	synonymous	Exon 4 of 10	NP_004394.1	O60443-1
	GSDME	NM_001127454.2		c.-4G>A		5_prime_UTR	Exon 3 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.489G>A	p.Thr163Thr	synonymous	Exon 4 of 10	ENSP00000494186.1	O60443-1
	GSDME	ENST00000342947.9	TSL:1	c.489G>A	p.Thr163Thr	synonymous	Exon 4 of 10	ENSP00000339587.3	O60443-1
	GSDME	ENST00000419307.6	TSL:1	c.-4G>A		5_prime_UTR	Exon 3 of 9	ENSP00000401332.1	O60443-3

Frequencies

GnomAD3 genomes AF: 0.181 AC: 27464 AN: 152048 Hom.: 2868 Cov.: 33

Gnomad AFR AF: 0.208

Gnomad AMI AF: 0.120

Gnomad AMR AF: 0.140

Gnomad ASJ AF: 0.123

Gnomad EAS AF: 0.460

Gnomad SAS AF: 0.326

Gnomad FIN AF: 0.166

Gnomad MID AF: 0.155

Gnomad NFE AF: 0.148

Gnomad OTH AF: 0.171

GnomAD2 exomes AF: 0.200 AC: 50180 AN: 250932 AF XY: 0.205

Gnomad AFR exome AF: 0.208

Gnomad AMR exome AF: 0.154

Gnomad ASJ exome AF: 0.108

Gnomad EAS exome AF: 0.457

Gnomad FIN exome AF: 0.170

Gnomad NFE exome AF: 0.151

Gnomad OTH exome AF: 0.172

GnomAD4 exome AF: 0.173 AC: 252512 AN: 1461316 Hom.: 24935 Cov.: 52 AF XY: 0.177 AC XY: 128780 AN XY: 727006

African (AFR) AF: 0.208 AC: 6959 AN: 33476

American (AMR) AF: 0.150 AC: 6715 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.108 AC: 2833 AN: 26136

East Asian (EAS) AF: 0.437 AC: 17357 AN: 39700

South Asian (SAS) AF: 0.324 AC: 27986 AN: 86246

European-Finnish (FIN) AF: 0.174 AC: 9267 AN: 53138

Middle Eastern (MID) AF: 0.160 AC: 911 AN: 5684

European-Non Finnish (NFE) AF: 0.152 AC: 169428 AN: 1111836

Other (OTH) AF: 0.183 AC: 11056 AN: 60378

GnomAD4 genome AF: 0.181 AC: 27497 AN: 152166 Hom.: 2874 Cov.: 33 AF XY: 0.185 AC XY: 13744 AN XY: 74364

African (AFR) AF: 0.208 AC: 8642 AN: 41516

American (AMR) AF: 0.140 AC: 2136 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.123 AC: 428 AN: 3470

East Asian (EAS) AF: 0.460 AC: 2376 AN: 5164

South Asian (SAS) AF: 0.326 AC: 1568 AN: 4814

European-Finnish (FIN) AF: 0.166 AC: 1753 AN: 10582

Middle Eastern (MID) AF: 0.153 AC: 45 AN: 294

European-Non Finnish (NFE) AF: 0.148 AC: 10064 AN: 68004

Other (OTH) AF: 0.178 AC: 376 AN: 2112

Alfa AF: 0.159 Hom.: 3865

Bravo AF: 0.179

Asia WGS AF: 0.379 AC: 1319 AN: 3478

EpiCase AF: 0.147

EpiControl AF: 0.143

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Autosomal dominant nonsyndromic hearing loss 5 (2)
-	-	2	not specified (2)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	9.6
DANN	Benign	0.66
PhyloP100		0.51
PromoterAI		-0.044	Neutral
Mutation Taster		=99/1	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: rs754555; hg19: chr7-24758753; COSMIC: COSV61651115; COSMIC: COSV61651115;