chr7-24706249-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001127453.2(GSDME):​c.1118G>A​(p.Gly373Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000489 in 1,614,104 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00026 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000027 ( 0 hom. )

Consequence

GSDME
NM_001127453.2 missense

Scores

18

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 0.531
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.033106416).
BP6
Variant 7-24706249-C-T is Benign according to our data. Variant chr7-24706249-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 178334.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=2}.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000263 (40/152220) while in subpopulation AFR AF= 0.000965 (40/41468). AF 95% confidence interval is 0.000728. There are 0 homozygotes in gnomad4. There are 18 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
High AC in GnomAd4 at 40 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
GSDMENM_001127453.2 linkc.1118G>A p.Gly373Asp missense_variant 8/10 ENST00000645220.1 NP_001120925.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
GSDMEENST00000645220.1 linkc.1118G>A p.Gly373Asp missense_variant 8/10 NM_001127453.2 ENSP00000494186.1 O60443-1

Frequencies

GnomAD3 genomes
AF:
0.000263
AC:
40
AN:
152220
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000965
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.0000557
AC:
14
AN:
251442
Hom.:
0
AF XY:
0.0000147
AC XY:
2
AN XY:
135906
show subpopulations
Gnomad AFR exome
AF:
0.000800
Gnomad AMR exome
AF:
0.00
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:
0.00000879
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000267
AC:
39
AN:
1461884
Hom.:
0
Cov.:
31
AF XY:
0.0000206
AC XY:
15
AN XY:
727240
show subpopulations
Gnomad4 AFR exome
AF:
0.00105
Gnomad4 AMR exome
AF:
0.00
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:
0.00000270
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.000263
AC:
40
AN:
152220
Hom.:
0
Cov.:
33
AF XY:
0.000242
AC XY:
18
AN XY:
74364
show subpopulations
Gnomad4 AFR
AF:
0.000965
Gnomad4 AMR
AF:
0.00
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
Alfa
AF:
0.0000683
Hom.:
0
Bravo
AF:
0.000257
ESP6500AA
AF:
0.000681
AC:
3
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000576
AC:
7

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Benign:2
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 16, 2024- -
Likely benign, criteria provided, single submitterclinical testingGeneDxFeb 13, 2019- -
not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineJun 03, 2014Variant classified as Uncertain Significance - Favor Benign. The Gly373Asp varia nt in DFNA5 has not been previously reported in individuals with hearing loss, b ut has been identified in 0.07% (3/4406) of African American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/;dbSNP rs146399 987). The glycine (Gly) at position 373 is not well conserved across species and the change to an aspartate (Asp) has been identified in dogs, suggesting that t his variant might be tolerated. Other computational prediction tools suggest tha t the Gly373Asp variant may not impact the protein, though this information is n ot predictive enough to rule out pathogenicity. In summary, the clinical signifi cance of this variant cannot be determined with certainty; however based upon th e arguments described above, we would lean towards a more likely benign role. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.11
BayesDel_addAF
Benign
-0.39
T
BayesDel_noAF
Benign
-0.40
CADD
Benign
5.0
DANN
Benign
0.43
DEOGEN2
Benign
0.11
T;T;.;.;T
Eigen
Benign
-0.89
Eigen_PC
Benign
-0.93
FATHMM_MKL
Benign
0.043
N
LIST_S2
Benign
0.58
.;.;.;T;T
M_CAP
Benign
0.015
T
MetaRNN
Benign
0.033
T;T;T;T;T
MetaSVM
Benign
-1.0
T
PrimateAI
Benign
0.28
T
PROVEAN
Benign
-1.1
N;.;N;N;N
REVEL
Benign
0.089
Sift
Benign
0.22
T;.;T;T;T
Sift4G
Benign
0.63
T;.;T;T;T
Polyphen
0.20
B;B;.;.;B
Vest4
0.22
MVP
0.67
MPC
0.052
ClinPred
0.015
T
GERP RS
1.8
Varity_R
0.030
gMVP
0.31

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.030
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.

Other links and lift over

dbSNP: rs146399987; hg19: chr7-24745868; API