rs876305

Variant names:

• chr7-24719176-T-C
• rs876305
• NM_001127453.2:c.447A>G

Your query was ambiguous. Multiple possible variants found:

• chr7-24719176-T-C
• chr7-24719176-T-A
• chr7-24719176-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.447A>G​(p.Glu149Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.485 in 1,611,166 control chromosomes in the GnomAD database, including 206,645 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.57 (27315 hom., cov: 33)
  • Exomes 𝑓: 0.48 (179330 hom.)
• Consequence: GSDME NM_001127453.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.873
• Publications: 36 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=-0.74).
• BP6: Variant 7-24719176-T-C is Benign according to our data. Variant chr7-24719176-T-C is described in ClinVar as Benign. ClinVar VariationId is 44844.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.873 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.967 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.447A>G	p.Glu149Glu	synonymous	Exon 4 of 10	NP_001120925.1	O60443-1
	GSDME	NM_004403.3		c.447A>G	p.Glu149Glu	synonymous	Exon 4 of 10	NP_004394.1	O60443-1
	GSDME	NM_001127454.2		c.-46A>G		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.447A>G	p.Glu149Glu	synonymous	Exon 4 of 10	ENSP00000494186.1	O60443-1
	GSDME	ENST00000342947.9	TSL:1	c.447A>G	p.Glu149Glu	synonymous	Exon 4 of 10	ENSP00000339587.3	O60443-1
	GSDME	ENST00000419307.6	TSL:1	c.-46A>G		5_prime_UTR	Exon 3 of 9	ENSP00000401332.1	O60443-3

Frequencies

GnomAD3 genomes AF: 0.571 AC: 86843 AN: 152014 Hom.: 27250 Cov.: 33

Gnomad AFR AF: 0.781

Gnomad AMI AF: 0.260

Gnomad AMR AF: 0.619

Gnomad ASJ AF: 0.384

Gnomad EAS AF: 0.989

Gnomad SAS AF: 0.722

Gnomad FIN AF: 0.455

Gnomad MID AF: 0.510

Gnomad NFE AF: 0.424

Gnomad OTH AF: 0.531

GnomAD2 exomes AF: 0.570 AC: 142708 AN: 250270 AF XY: 0.559

Gnomad AFR exome AF: 0.788

Gnomad AMR exome AF: 0.739

Gnomad ASJ exome AF: 0.382

Gnomad EAS exome AF: 0.992

Gnomad FIN exome AF: 0.453

Gnomad NFE exome AF: 0.423

Gnomad OTH exome AF: 0.513

GnomAD4 exome AF: 0.476 AC: 694100 AN: 1459034 Hom.: 179330 Cov.: 52 AF XY: 0.480 AC XY: 348534 AN XY: 725948

African (AFR) AF: 0.795 AC: 26583 AN: 33444

American (AMR) AF: 0.722 AC: 32274 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.379 AC: 9890 AN: 26126

East Asian (EAS) AF: 0.996 AC: 39529 AN: 39700

South Asian (SAS) AF: 0.706 AC: 60822 AN: 86176

European-Finnish (FIN) AF: 0.462 AC: 24328 AN: 52700

Middle Eastern (MID) AF: 0.484 AC: 2767 AN: 5714

European-Non Finnish (NFE) AF: 0.421 AC: 466931 AN: 1110146

Other (OTH) AF: 0.514 AC: 30976 AN: 60308

GnomAD4 genome AF: 0.572 AC: 86968 AN: 152132 Hom.: 27315 Cov.: 33 AF XY: 0.581 AC XY: 43201 AN XY: 74372

African (AFR) AF: 0.781 AC: 32438 AN: 41514

American (AMR) AF: 0.619 AC: 9474 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.384 AC: 1333 AN: 3472

East Asian (EAS) AF: 0.989 AC: 5121 AN: 5176

South Asian (SAS) AF: 0.723 AC: 3484 AN: 4816

European-Finnish (FIN) AF: 0.455 AC: 4812 AN: 10576

Middle Eastern (MID) AF: 0.507 AC: 148 AN: 292

European-Non Finnish (NFE) AF: 0.424 AC: 28792 AN: 67966

Other (OTH) AF: 0.535 AC: 1129 AN: 2112

Alfa AF: 0.472 Hom.: 72732

Bravo AF: 0.589

Asia WGS AF: 0.842 AC: 2928 AN: 3478

EpiCase AF: 0.413

EpiControl AF: 0.403

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	-0.74
CADD	Benign	8.7
DANN	Benign	0.59
PhyloP100		0.87
PromoterAI		-0.038	Neutral
Mutation Taster		=300/0	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: rs876305; hg19: chr7-24758795; COSMIC: COSV61651807; COSMIC: COSV61651807;