Variant rs777408599 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 8P and 4B. PVS1BS2

The NM_001127453.2(GSDME):c.686_687insA(p.Asp229GlufsTer23) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000152 in 1,579,772 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. D229D) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000045 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

GSDME
NM_001127453.2 frameshift

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.01

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

BS2

High AC in GnomAd4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GSDME	NM_001127453.2 linkuse as main transcript	c.686_687insA	p.Asp229GlufsTer23	frameshift_variant	5/10	ENST00000645220.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GSDME	ENST00000645220.1 linkuse as main transcript	c.686_687insA	p.Asp229GlufsTer23	frameshift_variant	5/10		NM_001127453.2	P1	O60443-1

Frequencies

GnomAD3 genomes

AF:

0.0000451

AC:

AN:

132908

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000491

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000439

AC:

AN:

250602

Hom.:

AF XY:

0.0000517

AC XY:

AN XY:

135462

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000291

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.0000124

AC:

AN:

1446864

Hom.:

Cov.:

AF XY:

0.0000125

AC XY:

AN XY:

719396

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000251

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000118

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000181

Gnomad4 OTH exome

AF:

0.0000168

GnomAD4 genome

AF:

0.0000451

AC:

AN:

132908

Hom.:

Cov.:

AF XY:

0.0000932

AC XY:

AN XY:

64344

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000491

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000945

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 30, 2016

Variant classified as Uncertain Significance - Favor Benign. The p.Asp229fs vari ant in DFNA5 has not been previously reported in individuals with hearing loss, but has been identified in 11/35510 of Latino chromosomes by the Genome Aggregat ion Database (gnomAD, http://gnomad.broadinstitute.org/; dbSNP rs777408599). Thi s variant is predicted to cause a frameshift, which alters the protein?s amino a cid sequence beginning at position 229 and leads to a premature termination codo n 23 amino acids downstream. This alteration is then predicted to lead to a trun cated or absent protein. However, only variants resulting in altered splicing an d skipping of exon 8 have been reported to be causative for hearing loss through a gain of function mechanism of disease (Van Laer 2004). The p.Asp229fs variant is located in exon 5 of DFNA5 and is expected to result in loss of function (Lo F), which is not a known mechanism of hearing loss in this gene. In fact, a fram eshift variant in DFNA5 has been reported in members of an Iranian family, in wh ich the variant did not segregate with the hearing loss (Van Laer 2007). In summ ary, while the clinical significance of the p.Asp229fs variant is uncertain, its frequency in the general population and the lack of evidence supporting a LoF m echanism for hearing loss in DFNA5 suggests it is more likely to be benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over