rs1554767313
Variant summary
Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong
The NM_004408.4(DNM1):c.127G>A(p.Gly43Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/20 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G43D) has been classified as Likely pathogenic.
Frequency
Consequence
NM_004408.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 19 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DNM1 | NM_004408.4 | c.127G>A | p.Gly43Ser | missense_variant | 1/22 | ENST00000372923.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DNM1 | ENST00000372923.8 | c.127G>A | p.Gly43Ser | missense_variant | 1/22 | 1 | NM_004408.4 | A1 |
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1398472Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0AN XY: 695748
GnomAD4 genome Cov.: 31
ClinVar
Submissions by phenotype
Developmental and epileptic encephalopathy, 31 Pathogenic:4
Likely pathogenic, criteria provided, single submitter | clinical testing | Genetics and Molecular Pathology, SA Pathology | Mar 15, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | DASA | Jun 10, 2022 | The c.127G>A;p.(Gly43Ser) missense change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 520545; PMID: 26611353) - PS4. The variant was observed to have arisen de novo (paternity confirmed) in a patient with the disease and no family history (PMID: 26611353) - PS2. The variant is located in a mutational hot spot and/or critical and well-established functional domain (Dynamin_N) - PM1. This variant is not present in population databases:rs1554767313, gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is Pathogenic - |
Pathogenic, criteria provided, single submitter | research | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Mar 14, 2024 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | The missense variant p.G43S in DNM1 (NM_004408.4) has been previously reported as a de novo mutation in a patient with Lennox Gestaut syndrome.Protein modelling had revealed a damaging effect (Nakashima M et al,2016). The variant has been submitted to ClinVar as Pathogenic. The p.G43S variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The p.G43S missense variant is predicted to be damaging by both SIFT and PolyPhen2. The nucleotide c.127 in DNM1 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 30, 2015 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at