rs754553

Variant names:

• chr7-24719233-C-T
• rs754553
• NM_001127453.2:c.405-15G>A

Your query was ambiguous. Multiple possible variants found:

• chr7-24719233-C-T
• chr7-24719233-C-A
• chr7-24719233-C-G

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.405-15G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.172 in 1,598,224 control chromosomes in the GnomAD database, including 27,573 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (2879 hom., cov: 32)
  • Exomes 𝑓: 0.17 (24694 hom.)
• Consequence: GSDME NM_001127453.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -2.37
• Publications: 17 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=-0.9).
• BP6: Variant 7-24719233-C-T is Benign according to our data. Variant chr7-24719233-C-T is described in ClinVar as Benign. ClinVar VariationId is 44842.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.446 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.405-15G>A		intron	N/A	NP_001120925.1	O60443-1
	GSDME	NM_004403.3		c.405-15G>A		intron	N/A	NP_004394.1	O60443-1
	GSDME	NM_001127454.2		c.-88-15G>A		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.405-15G>A		intron	N/A	ENSP00000494186.1	O60443-1
	GSDME	ENST00000342947.9	TSL:1	c.405-15G>A		intron	N/A	ENSP00000339587.3	O60443-1
	GSDME	ENST00000419307.6	TSL:1	c.-88-15G>A		intron	N/A	ENSP00000401332.1	O60443-3

Frequencies

GnomAD3 genomes AF: 0.181 AC: 27475 AN: 152008 Hom.: 2873 Cov.: 32

Gnomad AFR AF: 0.208

Gnomad AMI AF: 0.120

Gnomad AMR AF: 0.140

Gnomad ASJ AF: 0.123

Gnomad EAS AF: 0.462

Gnomad SAS AF: 0.326

Gnomad FIN AF: 0.166

Gnomad MID AF: 0.155

Gnomad NFE AF: 0.148

Gnomad OTH AF: 0.170

GnomAD2 exomes AF: 0.200 AC: 48731 AN: 243396 AF XY: 0.205

Gnomad AFR exome AF: 0.208

Gnomad AMR exome AF: 0.154

Gnomad ASJ exome AF: 0.108

Gnomad EAS exome AF: 0.458

Gnomad FIN exome AF: 0.164

Gnomad NFE exome AF: 0.151

Gnomad OTH exome AF: 0.171

GnomAD4 exome AF: 0.171 AC: 246595 AN: 1446098 Hom.: 24694 Cov.: 35 AF XY: 0.175 AC XY: 125998 AN XY: 719976

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.206 AC: 6852 AN: 33268

American (AMR) AF: 0.150 AC: 6703 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.108 AC: 2808 AN: 26090

East Asian (EAS) AF: 0.437 AC: 17316 AN: 39604

South Asian (SAS) AF: 0.323 AC: 27770 AN: 85902

European-Finnish (FIN) AF: 0.170 AC: 7959 AN: 46816

Middle Eastern (MID) AF: 0.159 AC: 907 AN: 5710

European-Non Finnish (NFE) AF: 0.150 AC: 165389 AN: 1103968

Other (OTH) AF: 0.181 AC: 10891 AN: 60042

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.181 AC: 27508 AN: 152126 Hom.: 2879 Cov.: 32 AF XY: 0.185 AC XY: 13762 AN XY: 74366

African (AFR) AF: 0.208 AC: 8638 AN: 41484

American (AMR) AF: 0.140 AC: 2133 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.123 AC: 428 AN: 3472

East Asian (EAS) AF: 0.462 AC: 2385 AN: 5164

South Asian (SAS) AF: 0.326 AC: 1573 AN: 4820

European-Finnish (FIN) AF: 0.166 AC: 1760 AN: 10576

Middle Eastern (MID) AF: 0.153 AC: 45 AN: 294

European-Non Finnish (NFE) AF: 0.148 AC: 10062 AN: 68010

Other (OTH) AF: 0.178 AC: 375 AN: 2112

Alfa AF: 0.121 Hom.: 378

Bravo AF: 0.179

Asia WGS AF: 0.380 AC: 1320 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.081
DANN	Benign	0.31
PhyloP100		-2.4
PromoterAI		-0.070	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs754553; hg19: chr7-24758852; COSMIC: COSV61651769; COSMIC: COSV61651769;