7-24698545-C-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001127453.2(GSDME):c.*481G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.124 in 233,506 control chromosomes in the GnomAD database, including 1,921 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.13 (1242 hom., cov: 32)
  • Exomes 𝑓: 0.12 (679 hom.)
• Consequence: GSDME NM_001127453.2 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.784

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 7-24698545-C-G is Benign according to our data. Variant chr7-24698545-C-G is described in ClinVar as [Benign]. Clinvar id is 359825.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.136 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GSDME	NM_001127453.2	c.*481G>C		3_prime_UTR_variant	10/10	ENST00000645220.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GSDME	ENST00000645220.1	c.*481G>C		3_prime_UTR_variant	10/10		NM_001127453.2	P1

Frequencies

GnomAD3 genomes AF: 0.125 AC: 19082 AN: 152066 Hom.: 1241 Cov.: 32

Gnomad AFR AF: 0.126

Gnomad AMI AF: 0.0835

Gnomad AMR AF: 0.140

Gnomad ASJ AF: 0.0755

Gnomad EAS AF: 0.0575

Gnomad SAS AF: 0.132

Gnomad FIN AF: 0.114

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.132

Gnomad OTH AF: 0.110

GnomAD4 exome AF: 0.121 AC: 9842 AN: 81322 Hom.: 679 Cov.: 0 AF XY: 0.118 AC XY: 4928 AN XY: 41760

Gnomad4 AFR exome AF: 0.105

Gnomad4 AMR exome AF: 0.176

Gnomad4 ASJ exome AF: 0.0677

Gnomad4 EAS exome AF: 0.0493

Gnomad4 SAS exome AF: 0.115

Gnomad4 FIN exome AF: 0.114

Gnomad4 NFE exome AF: 0.127

Gnomad4 OTH exome AF: 0.123

GnomAD4 genome AF: 0.126 AC: 19101 AN: 152184 Hom.: 1242 Cov.: 32 AF XY: 0.123 AC XY: 9130 AN XY: 74376

Gnomad4 AFR AF: 0.126

Gnomad4 AMR AF: 0.141

Gnomad4 ASJ AF: 0.0755

Gnomad4 EAS AF: 0.0579

Gnomad4 SAS AF: 0.132

Gnomad4 FIN AF: 0.114

Gnomad4 NFE AF: 0.132

Gnomad4 OTH AF: 0.108

Alfa AF: 0.0722 Hom.: 90

Bravo AF: 0.126

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal dominant nonsyndromic hearing loss 5 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
Cadd	Benign	0.63
Dann	Benign	0.66

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

Publications

LitVar

Other links and lift over

dbSNP: rs12979; hg19: chr7-24738164;