chr7-24698540-A-ATACTC

Variant names:

• chr7-24698540-A-ATACTC
• rs201456060
• NM_001127453.2:c.*481_*485dupGAGTA

Variant summary

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

The NM_001127453.2(GSDME):​c.*481_*485dupGAGTA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0385 in 207,176 control chromosomes in the GnomAD database, including 218 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.038 (153 hom., cov: 32)
  • Exomes 𝑓: 0.039 (65 hom.)
• Consequence: GSDME NM_001127453.2 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.248
• 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 7-24698540-A-ATACTC is Benign according to our data. Variant chr7-24698540-A-ATACTC is described in ClinVar as Likely_benign. ClinVar VariationId is 359824.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0553 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.*481_*485dupGAGTA		3_prime_UTR	Exon 10 of 10	NP_001120925.1	O60443-1
	GSDME	NM_004403.3		c.*481_*485dupGAGTA		3_prime_UTR	Exon 10 of 10	NP_004394.1	O60443-1
	GSDME	NM_001127454.2		c.*481_*485dupGAGTA		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.*481_*485dupGAGTA		3_prime_UTR	Exon 10 of 10	ENSP00000494186.1	O60443-1
	GSDME	ENST00000342947.9	TSL:1	c.*481_*485dupGAGTA		3_prime_UTR	Exon 10 of 10	ENSP00000339587.3	O60443-1
	GSDME	ENST00000419307.6	TSL:1	c.*481_*485dupGAGTA		3_prime_UTR	Exon 9 of 9	ENSP00000401332.1	O60443-3

Frequencies

GnomAD3 genomes AF: 0.0383 AC: 5834 AN: 152134 Hom.: 153 Cov.: 32

Gnomad AFR AF: 0.00910

Gnomad AMI AF: 0.0374

Gnomad AMR AF: 0.0323

Gnomad ASJ AF: 0.0738

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0230

Gnomad FIN AF: 0.0572

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0568

Gnomad OTH AF: 0.0387

GnomAD4 exome AF: 0.0392 AC: 2153 AN: 54924 Hom.: 65 Cov.: 0 AF XY: 0.0383 AC XY: 1065 AN XY: 27840

African (AFR) AF: 0.00924 AC: 9 AN: 974

American (AMR) AF: 0.0347 AC: 123 AN: 3540

Ashkenazi Jewish (ASJ) AF: 0.0656 AC: 81 AN: 1234

East Asian (EAS) AF: 0.00 AC: 0 AN: 2752

South Asian (SAS) AF: 0.0212 AC: 145 AN: 6824

European-Finnish (FIN) AF: 0.0403 AC: 107 AN: 2656

Middle Eastern (MID) AF: 0.0238 AC: 5 AN: 210

European-Non Finnish (NFE) AF: 0.0466 AC: 1572 AN: 33710

Other (OTH) AF: 0.0367 AC: 111 AN: 3024

GnomAD4 genome AF: 0.0383 AC: 5832 AN: 152252 Hom.: 153 Cov.: 32 AF XY: 0.0372 AC XY: 2773 AN XY: 74452

African (AFR) AF: 0.00907 AC: 377 AN: 41556

American (AMR) AF: 0.0322 AC: 492 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0738 AC: 256 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.0226 AC: 109 AN: 4828

European-Finnish (FIN) AF: 0.0572 AC: 606 AN: 10600

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0568 AC: 3865 AN: 67998

Other (OTH) AF: 0.0388 AC: 82 AN: 2114

Alfa AF: 0.0462 Hom.: 17

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		-0.25
Mutation Taster		=100/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs201456060; hg19: chr7-24738159;