NM_001127453.2:c.863-6T>C

Variant names:

• chr7-24708260-A-G
• rs55735863
• NM_001127453.2:c.863-6T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001127453.2(GSDME):​c.863-6T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0515 in 1,613,916 control chromosomes in the GnomAD database, including 2,473 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.039 (157 hom., cov: 32)
  • Exomes 𝑓: 0.053 (2316 hom.)
• Consequence: GSDME NM_001127453.2 splice_region, intron
• Scores: Splicing: ADA: 0.00002882
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.142
• Publications: 5 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 7-24708260-A-G is Benign according to our data. Variant chr7-24708260-A-G is described in ClinVar as Benign. ClinVar VariationId is 44848.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0555 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.863-6T>C		splice_region intron	N/A	NP_001120925.1	O60443-1
	GSDME	NM_004403.3		c.863-6T>C		splice_region intron	N/A	NP_004394.1	O60443-1
	GSDME	NM_001127454.2		c.371-6T>C		splice_region intron	N/A	NP_001120926.1	O60443-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GSDME	ENST00000645220.1	MANE Select	c.863-6T>C		splice_region intron	N/A	ENSP00000494186.1	O60443-1
	GSDME	ENST00000342947.9	TSL:1	c.863-6T>C		splice_region intron	N/A	ENSP00000339587.3	O60443-1
	GSDME	ENST00000419307.6	TSL:1	c.371-6T>C		splice_region intron	N/A	ENSP00000401332.1	O60443-3

Frequencies

GnomAD3 genomes AF: 0.0386 AC: 5869 AN: 152196 Hom.: 156 Cov.: 32

Gnomad AFR AF: 0.00955

Gnomad AMI AF: 0.0373

Gnomad AMR AF: 0.0321

Gnomad ASJ AF: 0.0729

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0228

Gnomad FIN AF: 0.0576

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0570

Gnomad OTH AF: 0.0398

GnomAD2 exomes AF: 0.0435 AC: 10929 AN: 251222 AF XY: 0.0448

Gnomad AFR exome AF: 0.00825

Gnomad AMR exome AF: 0.0263

Gnomad ASJ exome AF: 0.0714

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.0615

Gnomad NFE exome AF: 0.0583

Gnomad OTH exome AF: 0.0507

GnomAD4 exome AF: 0.0528 AC: 77230 AN: 1461602 Hom.: 2316 Cov.: 31 AF XY: 0.0521 AC XY: 37892 AN XY: 727106

African (AFR) AF: 0.00750 AC: 251 AN: 33478

American (AMR) AF: 0.0275 AC: 1230 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0728 AC: 1902 AN: 26134

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39700

South Asian (SAS) AF: 0.0292 AC: 2519 AN: 86226

European-Finnish (FIN) AF: 0.0578 AC: 3085 AN: 53362

Middle Eastern (MID) AF: 0.0473 AC: 267 AN: 5640

European-Non Finnish (NFE) AF: 0.0585 AC: 65004 AN: 1111976

Other (OTH) AF: 0.0492 AC: 2967 AN: 60366

GnomAD4 genome AF: 0.0385 AC: 5870 AN: 152314 Hom.: 157 Cov.: 32 AF XY: 0.0374 AC XY: 2789 AN XY: 74482

African (AFR) AF: 0.00960 AC: 399 AN: 41576

American (AMR) AF: 0.0320 AC: 489 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0729 AC: 253 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5188

South Asian (SAS) AF: 0.0224 AC: 108 AN: 4828

European-Finnish (FIN) AF: 0.0576 AC: 612 AN: 10622

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

European-Non Finnish (NFE) AF: 0.0570 AC: 3880 AN: 68022

Other (OTH) AF: 0.0398 AC: 84 AN: 2110

Alfa AF: 0.0524 Hom.: 98

Bravo AF: 0.0359

Asia WGS AF: 0.0130 AC: 46 AN: 3478

EpiCase AF: 0.0622

EpiControl AF: 0.0569

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	-0.83
CADD	Benign	0.75
DANN	Benign	0.48
PhyloP100		0.14
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000029
dbscSNV1_RF	Benign	0.0
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: rs55735863; hg19: chr7-24747879;