rs17149912

Variant names:

• chr7-24702817-T-C
• rs17149912
• NM_001127453.2:c.1200A>G

Your query was ambiguous. Multiple possible variants found:

• chr7-24702817-T-C
• chr7-24702817-T-G

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.1200A>G​(p.Ala400Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.166 in 1,612,490 control chromosomes in the GnomAD database, including 24,394 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2310 hom., cov: 33)
  • Exomes 𝑓: 0.17 (22084 hom.)
• Consequence: GSDME NM_001127453.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.285
• Publications: 20 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=-0.86).
• BP6: Variant 7-24702817-T-C is Benign according to our data. Variant chr7-24702817-T-C is described in ClinVar as Benign. ClinVar VariationId is 44840.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.285 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.255 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.1200A>G	p.Ala400Ala	synonymous	Exon 9 of 10	NP_001120925.1	O60443-1
	GSDME	NM_004403.3		c.1200A>G	p.Ala400Ala	synonymous	Exon 9 of 10	NP_004394.1	O60443-1
	GSDME	NM_001127454.2		c.708A>G	p.Ala236Ala	synonymous	Exon 8 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.1200A>G	p.Ala400Ala	synonymous	Exon 9 of 10	ENSP00000494186.1	O60443-1
	GSDME	ENST00000342947.9	TSL:1	c.1200A>G	p.Ala400Ala	synonymous	Exon 9 of 10	ENSP00000339587.3	O60443-1
	GSDME	ENST00000419307.6	TSL:1	c.708A>G	p.Ala236Ala	synonymous	Exon 8 of 9	ENSP00000401332.1	O60443-3

Frequencies

GnomAD3 genomes AF: 0.168 AC: 25534 AN: 152104 Hom.: 2312 Cov.: 33

Gnomad AFR AF: 0.126

Gnomad AMI AF: 0.0593

Gnomad AMR AF: 0.254

Gnomad ASJ AF: 0.185

Gnomad EAS AF: 0.267

Gnomad SAS AF: 0.231

Gnomad FIN AF: 0.212

Gnomad MID AF: 0.241

Gnomad NFE AF: 0.155

Gnomad OTH AF: 0.174

GnomAD2 exomes AF: 0.201 AC: 50594 AN: 251402 AF XY: 0.197

Gnomad AFR exome AF: 0.129

Gnomad AMR exome AF: 0.324

Gnomad ASJ exome AF: 0.188

Gnomad EAS exome AF: 0.278

Gnomad FIN exome AF: 0.205

Gnomad NFE exome AF: 0.155

Gnomad OTH exome AF: 0.201

GnomAD4 exome AF: 0.166 AC: 242933 AN: 1460268 Hom.: 22084 Cov.: 31 AF XY: 0.169 AC XY: 122671 AN XY: 726456

African (AFR) AF: 0.128 AC: 4267 AN: 33444

American (AMR) AF: 0.314 AC: 14010 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.184 AC: 4794 AN: 26098

East Asian (EAS) AF: 0.289 AC: 11464 AN: 39622

South Asian (SAS) AF: 0.230 AC: 19826 AN: 86182

European-Finnish (FIN) AF: 0.206 AC: 10947 AN: 53254

Middle Eastern (MID) AF: 0.242 AC: 1390 AN: 5752

European-Non Finnish (NFE) AF: 0.149 AC: 165705 AN: 1110920

Other (OTH) AF: 0.175 AC: 10530 AN: 60308

GnomAD4 genome AF: 0.168 AC: 25539 AN: 152222 Hom.: 2310 Cov.: 33 AF XY: 0.176 AC XY: 13098 AN XY: 74416

African (AFR) AF: 0.126 AC: 5234 AN: 41536

American (AMR) AF: 0.254 AC: 3884 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.185 AC: 642 AN: 3472

East Asian (EAS) AF: 0.267 AC: 1380 AN: 5172

South Asian (SAS) AF: 0.233 AC: 1122 AN: 4824

European-Finnish (FIN) AF: 0.212 AC: 2246 AN: 10590

Middle Eastern (MID) AF: 0.238 AC: 70 AN: 294

European-Non Finnish (NFE) AF: 0.155 AC: 10544 AN: 68016

Other (OTH) AF: 0.172 AC: 363 AN: 2114

Alfa AF: 0.148 Hom.: 3836

Bravo AF: 0.169

Asia WGS AF: 0.253 AC: 878 AN: 3478

EpiCase AF: 0.160

EpiControl AF: 0.157

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	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	-0.86
CADD	Benign	4.8
DANN	Benign	0.42
PhyloP100		-0.28
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: rs17149912; hg19: chr7-24742436; COSMIC: COSV61651248; COSMIC: COSV61651248;