chr12-32731069-G-A
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 6P and 1B. PM1PM2PP2PP5BP4
The NM_001278464.2(DNM1L):c.1174G>A(p.Glu392Lys) 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 benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (no stars).
Frequency
Genomes: not found (cov: 33)
Consequence
DNM1L
NM_001278464.2 missense
NM_001278464.2 missense
Scores
6
5
7
Clinical Significance
Conservation
PhyloP100: 9.74
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]
YARS2 (HGNC:24249): (tyrosyl-tRNA synthetase 2) This gene encodes a mitochondrial protein that catalyzes the attachment of tyrosine to tRNA(Tyr). Mutations in this gene are associated with myopathy with lactic acidosis and sideroblastic anemia type 2 (MLASA2). [provided by RefSeq, Jan 2011]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 5 ACMG points.
PM1
?
In a region_of_interest Middle domain (size 145) in uniprot entity DNM1L_HUMAN there are 27 pathogenic changes around while only 1 benign (96%) in NM_001278464.2
PM2
?
Very rare variant in population databases, with high coverage;
PP2
?
Missense variant where missense usually causes diseases, DNM1L
PP5
?
Variant 12-32731069-G-A is Pathogenic according to our data. Variant chr12-32731069-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 374321.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr12-32731069-G-A is described in Lovd as [Pathogenic].
BP4
?
Computational evidence support a benign effect (MetaRNN=0.3597831).. Strength limited to SUPPORTING due to the PP5.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DNM1L | NM_001278464.2 | c.1174G>A | p.Glu392Lys | missense_variant | 11/21 | ENST00000553257.6 | |
DNM1L | NM_012062.5 | c.1135G>A | p.Glu379Lys | missense_variant | 10/20 | ENST00000549701.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DNM1L | ENST00000553257.6 | c.1174G>A | p.Glu392Lys | missense_variant | 11/21 | 2 | NM_001278464.2 | ||
DNM1L | ENST00000549701.6 | c.1135G>A | p.Glu379Lys | missense_variant | 10/20 | 1 | NM_012062.5 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome ? Cov.: 33
GnomAD4 genome
?
Cov.:
33
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link
Submissions by phenotype
Encephalopathy, lethal, due to defective mitochondrial peroxisomal fission 1 Pathogenic:1
Likely pathogenic, no assertion criteria provided | clinical testing | Baylor Genetics | Jun 23, 2014 | A de novo missense change in the DNM1L has been reported in an infant with a lethal encephalopathy due to defective mitochondrial and peroxisomal fission [OMIM:614388; PMID: 17460227]. The previously reported patient had a history of diminished fetal movements during pregnancy, and presented with poor feeding and neurologic impairment, including hypotonia, little spontaneous movement, no tendon reflexes, no response to light stimulation, and poor visual fixation, abnormal gyral pattern, dysmyelination, persistent lactic acidemia and mildly elevated plasma concentration of very long-chain fatty acids [PMID: 17460227]. Our lab has reported a de novo missense change in an individual with features that include hypotonia, apnea, lactic acidosis, and a prenatal history of intrauterine growth restriction, hydrocephalus, cystic kidneys and concern for aortic coarctation. A brain MRI showed microcephaly, simplified gyral pattern, diffuse reduction in the cerebral white matter volume, agenesis of the corpus callosum, marked lateral ventriculomegaly, volume loss and irregularity along the interior cerebellar hemispheres, and a small brainstem. A variant in PDHA1 (NM_001173455.1, c.448G>A) was also reported in this individual. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D;D;D;D;D;D;D
M_CAP
Benign
T
MetaRNN
Benign
T;T;T;T;T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
N;.;.;N;.;N;N;.
MutationTaster
Benign
D;D;D;D;D;D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D;D;D;D;D;D;D;D
REVEL
Uncertain
Sift
Benign
T;T;T;T;T;T;T;T
Sift4G
Benign
T;T;T;T;T;T;T;T
Polyphen
0.37
.;.;.;B;.;.;.;.
Vest4
MutPred
Gain of ubiquitination at E379 (P = 0.0247);.;.;Gain of ubiquitination at E379 (P = 0.0247);.;Gain of ubiquitination at E379 (P = 0.0247);Gain of ubiquitination at E379 (P = 0.0247);.;
MVP
MPC
1.3
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