chr7-24699045-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_001127453.2(GSDME):ā€‹c.1472T>Cā€‹(p.Leu491Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,459,682 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 0.0000014 ( 0 hom. )

Consequence

GSDME
NM_001127453.2 missense

Scores

5
7
6

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.24
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.777

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
GSDMENM_001127453.2 linkuse as main transcriptc.1472T>C p.Leu491Ser missense_variant 10/10 ENST00000645220.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
GSDMEENST00000645220.1 linkuse as main transcriptc.1472T>C p.Leu491Ser missense_variant 10/10 NM_001127453.2 P1O60443-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1459682
Hom.:
0
Cov.:
30
AF XY:
0.00
AC XY:
0
AN XY:
726332
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGeneDxJul 27, 2022Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.75
BayesDel_addAF
Pathogenic
0.25
D
BayesDel_noAF
Uncertain
0.13
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Benign
0.40
T;T;.;.;T
Eigen
Uncertain
0.49
Eigen_PC
Uncertain
0.42
FATHMM_MKL
Benign
0.73
D
LIST_S2
Benign
0.61
.;.;.;T;T
M_CAP
Uncertain
0.14
D
MetaRNN
Pathogenic
0.78
D;D;D;D;D
MetaSVM
Uncertain
-0.044
T
MutationTaster
Benign
1.0
N;N;N;N;N
PrimateAI
Benign
0.38
T
PROVEAN
Benign
-2.3
N;.;D;D;N
REVEL
Uncertain
0.59
Sift
Pathogenic
0.0
D;.;D;D;D
Sift4G
Pathogenic
0.0
D;.;D;D;D
Polyphen
1.0
D;D;.;.;D
Vest4
0.93
MutPred
0.67
Loss of stability (P = 0.0077);Loss of stability (P = 0.0077);.;.;Loss of stability (P = 0.0077);
MVP
0.97
MPC
0.30
ClinPred
0.97
D
GERP RS
5.4
Varity_R
0.34
gMVP
0.82

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-24738664; API