rs144358787

Variant names:

• chr7-24708253-C-T
• rs144358787
• NM_001127453.2:c.864G>A

Your query was ambiguous. Multiple possible variants found:

• chr7-24708253-C-T
• chr7-24708253-C-A
• chr7-24708253-C-G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001127453.2(GSDME):​c.864G>A​(p.Ala288Ala) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00112 in 1,613,964 control chromosomes in the GnomAD database, including 11 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 0.00089 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (11 hom.)
• Consequence: GSDME NM_001127453.2 splice_region, synonymous
• Scores: Splicing: ADA: 0.00003386
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -2.76
• Publications: 4 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 (REVEL=0.008).
• BP6: Variant 7-24708253-C-T is Benign according to our data. Variant chr7-24708253-C-T is described in ClinVar as Benign. ClinVar VariationId is 359844.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.76 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000893 (136/152316) while in subpopulation SAS AF = 0.0056 (27/4822). AF 95% confidence interval is 0.00395. There are 0 homozygotes in GnomAd4. There are 65 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 136 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.864G>A	p.Ala288Ala	splice_region synonymous	Exon 7 of 10	NP_001120925.1	O60443-1
	GSDME	NM_004403.3		c.864G>A	p.Ala288Ala	splice_region synonymous	Exon 7 of 10	NP_004394.1	O60443-1
	GSDME	NM_001127454.2		c.372G>A	p.Ala124Ala	splice_region synonymous	Exon 6 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.864G>A	p.Ala288Ala	splice_region synonymous	Exon 7 of 10	ENSP00000494186.1	O60443-1
	GSDME	ENST00000342947.9	TSL:1	c.864G>A	p.Ala288Ala	splice_region synonymous	Exon 7 of 10	ENSP00000339587.3	O60443-1
	GSDME	ENST00000419307.6	TSL:1	c.372G>A	p.Ala124Ala	splice_region synonymous	Exon 6 of 9	ENSP00000401332.1	O60443-3

Frequencies

GnomAD3 genomes AF: 0.000894 AC: 136 AN: 152198 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00559

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00123

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.00125 AC: 314 AN: 251294 AF XY: 0.00163

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000417

Gnomad NFE exome AF: 0.000967

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.00114 AC: 1670 AN: 1461648 Hom.: 11 Cov.: 30 AF XY: 0.00130 AC XY: 942 AN XY: 727116

African (AFR) AF: 0.000179 AC: 6 AN: 33476

American (AMR) AF: 0.0000895 AC: 4 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00588 AC: 507 AN: 86194

European-Finnish (FIN) AF: 0.000375 AC: 20 AN: 53390

Middle Eastern (MID) AF: 0.00282 AC: 16 AN: 5668

European-Non Finnish (NFE) AF: 0.000924 AC: 1028 AN: 1111990

Other (OTH) AF: 0.00147 AC: 89 AN: 60380

GnomAD4 genome AF: 0.000893 AC: 136 AN: 152316 Hom.: 0 Cov.: 32 AF XY: 0.000873 AC XY: 65 AN XY: 74492

African (AFR) AF: 0.000337 AC: 14 AN: 41570

American (AMR) AF: 0.000392 AC: 6 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00560 AC: 27 AN: 4822

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10626

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00123 AC: 84 AN: 68028

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.000953 Hom.: 2

Bravo AF: 0.000604

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00131

EpiControl AF: 0.00130

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Autosomal dominant nonsyndromic hearing loss 5 (1)
-	-	1	GSDME-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.90
DANN	Benign	0.83
PhyloP100		-2.8
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000034
dbscSNV1_RF	Benign	0.0040
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: rs144358787; hg19: chr7-24747872;