NM_001278464.2:c.1174G>A

Variant names:

• chr12-32731069-G-A
• rs1057518694
• NM_001278464.2:c.1174G>A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 6P and 1B. PM1 PM2 PP2 PP5 BP4

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
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• 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]

ACMG classification

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 10 pathogenic changes around while only 1 benign (91%) in NM_001278464.2
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the DNM1L gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 31 curated pathogenic missense variants (we use a threshold of 10). The gene has 9 curated benign missense variants. Gene score misZ: 3.8282 (above the threshold of 3.09). Trascript score misZ: 5.2186 (above the threshold of 3.09). GenCC associations: The gene is linked to encephalopathy, lethal, due to defective mitochondrial peroxisomal fission 1, encephalopathy due to mitochondrial and peroxisomal fission defect, optic atrophy 5, Leigh syndrome, autosomal dominant optic atrophy, classic form.
• 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 rank	MANE	Protein	UniProt
DNM1L	NM_001278464.2	c.1174G>A	p.Glu392Lys	missense_variant	Exon 11 of 21	ENST00000553257.6	NP_001265393.1
DNM1L	NM_012062.5	c.1135G>A	p.Glu379Lys	missense_variant	Exon 10 of 20	ENST00000549701.6	NP_036192.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNM1L	ENST00000553257.6	c.1174G>A	p.Glu392Lys	missense_variant	Exon 11 of 21	2	NM_001278464.2	ENSP00000449089.1
DNM1L	ENST00000549701.6	c.1135G>A	p.Glu379Lys	missense_variant	Exon 10 of 20	1	NM_012062.5	ENSP00000450399.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Encephalopathy, lethal, due to defective mitochondrial peroxisomal fission 1 Pathogenic:1

Jun 23, 2014

Baylor Genetics

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.23
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.75	.;.;.;D;D;.;.;.
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D;D;D
M_CAP	Benign	0.0092	T
MetaRNN	Benign	0.36	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.52	T
MutationAssessor	Benign	0.42	N;.;.;N;.;N;N;.
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-2.8	D;D;D;D;D;D;D;D
REVEL	Uncertain	0.49
Sift	Benign	0.15	T;T;T;T;T;T;T;T
Sift4G	Benign	0.40	T;T;T;T;T;T;T;T
Polyphen		0.37	.;.;.;B;.;.;.;.
Vest4		0.71
MutPred		0.51		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		0.75
MPC		1.3
ClinPred		0.87	D
GERP RS		4.9
Varity_R		0.64
gMVP		0.92

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1057518694; hg19: chr12-32884003;