rs879255687
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Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PVS1PP5
The NM_001278464.2(DNM1L):โc.385_386delโ(p.Glu129LysfsTer6) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000243 in 1,603,318 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: ๐ 0.000046 ( 0 hom., cov: 32)
Exomes ๐: 0.000022 ( 0 hom. )
Consequence
DNM1L
NM_001278464.2 frameshift
NM_001278464.2 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 5.42
Genes affected
DNM1L (HGNC:2973): (dynamin 1 like) This gene encodes a member of the dynamin superfamily of GTPases. The encoded protein mediates mitochondrial and peroxisomal division, and is involved in developmentally regulated apoptosis and programmed necrosis. Dysfunction of this gene is implicated in several neurological disorders, including Alzheimer's disease. Mutations in this gene are associated with the autosomal dominant disorder, encephalopathy, lethal, due to defective mitochondrial and peroxisomal fission (EMPF). Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jun 2013]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PP5
?
Variant 12-32708199-CAG-C is Pathogenic according to our data. Variant chr12-32708199-CAG-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 253264.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=2, Uncertain_significance=1}. Variant chr12-32708199-CAG-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DNM1L | NM_001278464.2 | c.385_386del | p.Glu129LysfsTer6 | frameshift_variant | 5/21 | ENST00000553257.6 | |
DNM1L | NM_012062.5 | c.346_347del | p.Glu116LysfsTer6 | frameshift_variant | 4/20 | ENST00000549701.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DNM1L | ENST00000549701.6 | c.346_347del | p.Glu116LysfsTer6 | frameshift_variant | 4/20 | 1 | NM_012062.5 | ||
DNM1L | ENST00000553257.6 | c.385_386del | p.Glu129LysfsTer6 | frameshift_variant | 5/21 | 2 | NM_001278464.2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000461 AC: 7AN: 151822Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000441 AC: 11AN: 249612Hom.: 0 AF XY: 0.0000370 AC XY: 5AN XY: 135272
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GnomAD4 exome AF: 0.0000220 AC: 32AN: 1451496Hom.: 0 AF XY: 0.0000221 AC XY: 16AN XY: 722662
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GnomAD4 genome ? AF: 0.0000461 AC: 7AN: 151822Hom.: 0 Cov.: 32 AF XY: 0.0000674 AC XY: 5AN XY: 74154
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:3Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Feb 20, 2024 | Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 26825290, 33742459, 35982159, 35562572, 34573276, 29877124, 33718295, 35741050, 27328748) - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 02, 2023 | This sequence change creates a premature translational stop signal (p.Glu116Lysfs*6) in the DNM1L gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DNM1L are known to be pathogenic (PMID: 26825290, 27328748). This variant is present in population databases (rs779230636, gnomAD 0.009%). This premature translational stop signal has been observed in individuals with autosomal recessive encephalopathy (PMID: 26825290, 27328748). It has also been observed to segregate with disease in related individuals. This variant is also known as NM_001278464.1:c.385_386del (p.Glu129Lys*6). ClinVar contains an entry for this variant (Variation ID: 253264). For these reasons, this variant has been classified as Pathogenic. - |
Encephalopathy, lethal, due to defective mitochondrial peroxisomal fission 1 Pathogenic:1Uncertain:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Aug 25, 2016 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory of Medical Genetics, National & Kapodistrian University of Athens | Oct 06, 2021 | PVS1, PM2 - |
Computational scores
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at