rs371054976

Variant names:

• chr7-24717264-G-A
• rs371054976
• NM_001127453.2:c.687C>T

Your query was ambiguous. Multiple possible variants found:

• chr7-24717264-G-A
• chr7-24717264-G-T

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP6_Moderate BP7 BS1 BS2

The NM_001127453.2(GSDME):​c.687C>T​(p.Asp229Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000443 in 1,579,772 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000030 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000046 (0 hom.)
• Consequence: GSDME NM_001127453.2 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.36
• Publications: 0 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 -11 ACMG points.

• BP6: Variant 7-24717264-G-A is Benign according to our data. Variant chr7-24717264-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 504976.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-1.36 with no splicing effect.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.0000456 (66/1446864) while in subpopulation MID AF = 0.000387 (2/5168). AF 95% confidence interval is 0.0000685. There are 0 homozygotes in GnomAdExome4. There are 35 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAdExome4 at 66 AD gene.

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.687C>T	p.Asp229Asp	synonymous	Exon 5 of 10	NP_001120925.1	O60443-1
	GSDME	NM_004403.3		c.687C>T	p.Asp229Asp	synonymous	Exon 5 of 10	NP_004394.1	O60443-1
	GSDME	NM_001127454.2		c.195C>T	p.Asp65Asp	synonymous	Exon 4 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.687C>T	p.Asp229Asp	synonymous	Exon 5 of 10	ENSP00000494186.1	O60443-1
	GSDME	ENST00000342947.9	TSL:1	c.687C>T	p.Asp229Asp	synonymous	Exon 5 of 10	ENSP00000339587.3	O60443-1
	GSDME	ENST00000419307.6	TSL:1	c.195C>T	p.Asp65Asp	synonymous	Exon 4 of 9	ENSP00000401332.1	O60443-3

Frequencies

GnomAD3 genomes AF: 0.0000301 AC: 4 AN: 132908 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000263

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000502

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000319 AC: 8 AN: 250602 AF XY: 0.0000369

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000582

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000441

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000456 AC: 66 AN: 1446864 Hom.: 0 Cov.: 32 AF XY: 0.0000487 AC XY: 35 AN XY: 719396

African (AFR) AF: 0.0000300 AC: 1 AN: 33288

American (AMR) AF: 0.0000228 AC: 1 AN: 43838

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25698

East Asian (EAS) AF: 0.0000261 AC: 1 AN: 38352

South Asian (SAS) AF: 0.0000118 AC: 1 AN: 84796

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51958

Middle Eastern (MID) AF: 0.000387 AC: 2 AN: 5168

European-Non Finnish (NFE) AF: 0.0000525 AC: 58 AN: 1104218

Other (OTH) AF: 0.0000336 AC: 2 AN: 59548

GnomAD4 genome AF: 0.0000301 AC: 4 AN: 132908 Hom.: 0 Cov.: 31 AF XY: 0.0000155 AC XY: 1 AN XY: 64344

African (AFR) AF: 0.0000263 AC: 1 AN: 38028

American (AMR) AF: 0.00 AC: 0 AN: 12228

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2980

East Asian (EAS) AF: 0.00 AC: 0 AN: 4342

South Asian (SAS) AF: 0.00 AC: 0 AN: 3846

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8774

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 240

European-Non Finnish (NFE) AF: 0.0000502 AC: 3 AN: 59786

Other (OTH) AF: 0.00 AC: 0 AN: 1820

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000227

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	0.48
DANN	Benign	0.44
PhyloP100		-1.4
PromoterAI		0.0018	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs371054976; hg19: chr7-24756883; COSMIC: COSV100742296;