rs77276759

Variant names:

• chr7-24698520-AT-A
• rs77276759
• NM_001127453.2:c.*505delA

Your query was ambiguous. Multiple possible variants found:

• chr7-24698520-AT-A
• chr7-24698520-AT-ATT

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_001127453.2(GSDME):​c.*505delA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0459 in 186,362 control chromosomes in the GnomAD database, including 549 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.053 (511 hom., cov: 32)
  • Exomes 𝑓: 0.016 (38 hom.)
• Consequence: GSDME NM_001127453.2 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.50
• 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: G2P, Labcorp Genetics (formerly Invitae)
• autosomal dominant nonsyndromic hearing loss

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP6: Variant 7-24698520-AT-A is Benign according to our data. Variant chr7-24698520-AT-A is described in ClinVar as Likely_benign. ClinVar VariationId is 359823.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.179 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.*505delA		3_prime_UTR	Exon 10 of 10	NP_001120925.1	O60443-1
	GSDME	NM_004403.3		c.*505delA		3_prime_UTR	Exon 10 of 10	NP_004394.1	O60443-1
	GSDME	NM_001127454.2		c.*505delA		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.*505delA		3_prime_UTR	Exon 10 of 10	ENSP00000494186.1	O60443-1
	GSDME	ENST00000342947.9	TSL:1	c.*505delA		3_prime_UTR	Exon 10 of 10	ENSP00000339587.3	O60443-1
	GSDME	ENST00000419307.6	TSL:1	c.*505delA		3_prime_UTR	Exon 9 of 9	ENSP00000401332.1	O60443-3

Frequencies

GnomAD3 genomes AF: 0.0525 AC: 7984 AN: 151940 Hom.: 508 Cov.: 32

Gnomad AFR AF: 0.131

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0652

Gnomad ASJ AF: 0.0332

Gnomad EAS AF: 0.189

Gnomad SAS AF: 0.0158

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.00409

Gnomad OTH AF: 0.0452

GnomAD4 exome AF: 0.0159 AC: 545 AN: 34304 Hom.: 38 Cov.: 0 AF XY: 0.0157 AC XY: 271 AN XY: 17264

African (AFR) AF: 0.107 AC: 41 AN: 384

American (AMR) AF: 0.0461 AC: 143 AN: 3100

Ashkenazi Jewish (ASJ) AF: 0.0189 AC: 12 AN: 636

East Asian (EAS) AF: 0.145 AC: 233 AN: 1606

South Asian (SAS) AF: 0.00643 AC: 25 AN: 3886

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1464

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 130

European-Non Finnish (NFE) AF: 0.00283 AC: 60 AN: 21186

Other (OTH) AF: 0.0162 AC: 31 AN: 1912

GnomAD4 genome AF: 0.0526 AC: 8004 AN: 152058 Hom.: 511 Cov.: 32 AF XY: 0.0535 AC XY: 3981 AN XY: 74366

African (AFR) AF: 0.131 AC: 5454 AN: 41520

American (AMR) AF: 0.0651 AC: 994 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.0332 AC: 115 AN: 3468

East Asian (EAS) AF: 0.189 AC: 975 AN: 5158

South Asian (SAS) AF: 0.0156 AC: 75 AN: 4820

European-Finnish (FIN) AF: 0.000283 AC: 3 AN: 10592

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.00409 AC: 278 AN: 67922

Other (OTH) AF: 0.0462 AC: 97 AN: 2100

Alfa AF: 0.0281 Hom.: 25

Bravo AF: 0.0610

Asia WGS AF: 0.0880 AC: 306 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Nonsyndromic Hearing Loss, Mixed (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.5
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: rs77276759; hg19: chr7-24738139;