NM_001127453.2:c.1331G>T
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
Consequence
NM_001127453.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -5 ACMG points.
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 exomes AF: 0.00000795 AC: 2AN: 251440Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135894
GnomAD4 exome AF: 0.00000958 AC: 14AN: 1461890Hom.: 0 Cov.: 31 AF XY: 0.0000151 AC XY: 11AN XY: 727246
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not specified Uncertain:1
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
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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at