chr7-24699186-C-A
Variant names:
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS1_SupportingBS2
The NM_001127453.2(GSDME):c.1331G>T(p.Arg444Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000958 in 1,461,890 control chromosomes in the GnomAD database, with no homozygous occurrence. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000096 ( 0 hom. )
Consequence
GSDME
NM_001127453.2 missense
NM_001127453.2 missense
Scores
3
15
Clinical Significance
Conservation
PhyloP100: -0.165
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 Likely_benign. Variant got -5 ACMG points.
BS1
Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00000958 (14/1461890) while in subpopulation MID AF= 0.00052 (3/5768). AF 95% confidence interval is 0.000141. There are 0 homozygotes in gnomad4_exome. There are 11 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
BS2
High AC in GnomAdExome4 at 14 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
GSDME | NM_001127453.2 | c.1331G>T | p.Arg444Met | missense_variant | Exon 10 of 10 | ENST00000645220.1 | NP_001120925.1 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD3 exomes AF: 0.00000795 AC: 2AN: 251440Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135894
GnomAD3 exomes
AF:
AC:
2
AN:
251440
Hom.:
AF XY:
AC XY:
2
AN XY:
135894
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.00000958 AC: 14AN: 1461890Hom.: 0 Cov.: 31 AF XY: 0.0000151 AC XY: 11AN XY: 727246
GnomAD4 exome
AF:
AC:
14
AN:
1461890
Hom.:
Cov.:
31
AF XY:
AC XY:
11
AN XY:
727246
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
Alfa
AF:
Hom.:
ExAC
AF:
AC:
1
EpiCase
AF:
EpiControl
AF:
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
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 | Mar 02, 2017 | The p.Arg444Met variant in DFNA5 has not been previously reported in individuals with hearing loss, but has been identified in 1/16486 of South Asian chromosome s by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbS NP rs780683974). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. Splice predictio n tools suggest that this variant may result in the creation of a cryptic splice site, though this information is not predictive enough to determine pathogenici ty. Additional computational prediction tools and conservation analysis do not p rovide strong support for or against an impact to the protein. Pathogenic varian ts in DFNA5 reported to date result in skipping of exon 8; however, this variant is located in exon 10. In summary, the clinical significance of the p.Arg444Met variant is uncertain. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 25, 2025 | This sequence change replaces arginine, which is basic and polar, with methionine, which is neutral and non-polar, at codon 444 of the DFNA5 protein (p.Arg444Met). This variant is present in population databases (rs780683974, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with DFNA5-related conditions. ClinVar contains an entry for this variant (Variation ID: 505547). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt DFNA5 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
DEOGEN2
Benign
T;T;.;.;T
Eigen
Uncertain
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Benign
.;.;.;T;T
M_CAP
Benign
T
MetaRNN
Uncertain
T;T;T;T;T
MetaSVM
Benign
T
PrimateAI
Benign
T
PROVEAN
Benign
N;.;N;N;N
REVEL
Benign
Sift
Benign
D;.;D;D;D
Sift4G
Uncertain
D;.;D;D;D
Polyphen
D;D;.;.;D
Vest4
MutPred
Gain of ubiquitination at K440 (P = 0.102);Gain of ubiquitination at K440 (P = 0.102);.;.;Gain of ubiquitination at K440 (P = 0.102);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at