rs758488919

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 8P and 4B. PVS1BS2

The NM_001127453.2(GSDME):​c.116_119delAAAA​(p.Lys39ArgfsTer24) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000434 in 1,614,062 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

GSDME
NM_001127453.2 frameshift

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.78

Publications

2 publications found
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 Gene-Disease associations (from GenCC):
  • autosomal dominant nonsyndromic hearing loss
    Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
  • autosomal dominant nonsyndromic hearing loss 5
    Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 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 GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
GSDMENM_001127453.2 linkc.116_119delAAAA p.Lys39ArgfsTer24 frameshift_variant Exon 2 of 10 ENST00000645220.1 NP_001120925.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
GSDMEENST00000645220.1 linkc.116_119delAAAA p.Lys39ArgfsTer24 frameshift_variant Exon 2 of 10 NM_001127453.2 ENSP00000494186.1 O60443-1

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152160
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000192
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
GnomAD2 exomes
AF:
0.0000119
AC:
3
AN:
251436
AF XY:
0.0000147
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000544
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000879
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000410
AC:
6
AN:
1461784
Hom.:
0
AF XY:
0.00000413
AC XY:
3
AN XY:
727200
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33480
American (AMR)
AF:
0.00
AC:
0
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26134
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39698
South Asian (SAS)
AF:
0.0000116
AC:
1
AN:
86258
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53388
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
0.00000360
AC:
4
AN:
1111938
Other (OTH)
AF:
0.0000166
AC:
1
AN:
60396
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.425
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152278
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74460
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41574
American (AMR)
AF:
0.00
AC:
0
AN:
15286
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3468
East Asian (EAS)
AF:
0.000193
AC:
1
AN:
5190
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4820
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10606
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
294
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
68014
Other (OTH)
AF:
0.00
AC:
0
AN:
2114
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.575
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
PhyloP100
6.8
Mutation Taster
=13/187
disease causing (fs/PTC)

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

Other links and lift over

dbSNP: rs758488919; hg19: chr7-24789274; API