7-24699002-C-T

Variant names:

• chr7-24699002-C-T
• rs199887441
• NM_001127453.2:c.*24G>A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001127453.2(GSDME):​c.*24G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000248 in 1,517,972 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00026 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00025 (1 hom.)
• Consequence: GSDME NM_001127453.2 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.985

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 7-24699002-C-T is Benign according to our data. Variant chr7-24699002-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 359837.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000256 (39/152340) while in subpopulation AMR AF= 0.00118 (18/15308). AF 95% confidence interval is 0.00076. There are 1 homozygotes in gnomad4. There are 21 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 39 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GSDME	NM_001127453.2	c.*24G>A		3_prime_UTR_variant	Exon 10 of 10	ENST00000645220.1	NP_001120925.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GSDME	ENST00000645220	c.*24G>A		3_prime_UTR_variant	Exon 10 of 10		NM_001127453.2	ENSP00000494186.1

Frequencies

GnomAD3 genomes AF: 0.000256 AC: 39 AN: 152222 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000404 AC: 98 AN: 242492 Hom.: 0 AF XY: 0.000336 AC XY: 44 AN XY: 130882

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00159

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000469

Gnomad NFE exome AF: 0.000313

Gnomad OTH exome AF: 0.00150

GnomAD4 exome AF: 0.000248 AC: 338 AN: 1365632 Hom.: 1 Cov.: 21 AF XY: 0.000227 AC XY: 155 AN XY: 684240

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00181

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000376

Gnomad4 NFE exome AF: 0.000235

Gnomad4 OTH exome AF: 0.000263

GnomAD4 genome AF: 0.000256 AC: 39 AN: 152340 Hom.: 1 Cov.: 32 AF XY: 0.000282 AC XY: 21 AN XY: 74496

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.00118

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000279

Gnomad4 OTH AF: 0.00

Bravo AF: 0.000374

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal dominant nonsyndromic hearing loss 5 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

not provided Benign:1

Aug 19, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.1
DANN	Benign	0.56

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: rs199887441; hg19: chr7-24738621; COSMIC: COSV56036629; COSMIC: COSV56036629;