12-32713327-C-A

Position:

• chr12-32713327-C-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP2 PP3_Strong PP5

The NM_012062.5(DNM1L):​c.575C>A​(p.Ala192Glu) 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. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DNM1L NM_012062.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.64

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]

DNM1L (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), DNM1L. . Gene score misZ 3.8282 (greater than the threshold 3.09). Trascript score misZ 5.3198 (greater than threshold 3.09). GenCC has associacion of gene with 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.951
• PP5: Variant 12-32713327-C-A is Pathogenic according to our data. Variant chr12-32713327-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 446170.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNM1L	NM_001278464.2	c.614C>A	p.Ala205Glu	missense_variant	7/21	ENST00000553257.6	NP_001265393.1
DNM1L	NM_012062.5	c.575C>A	p.Ala192Glu	missense_variant	6/20	ENST00000549701.6	NP_036192.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNM1L	ENST00000553257.6	c.614C>A	p.Ala205Glu	missense_variant	7/21	2	NM_001278464.2	ENSP00000449089.1
DNM1L	ENST00000549701.6	c.575C>A	p.Ala192Glu	missense_variant	6/20	1	NM_012062.5	ENSP00000450399.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Optic atrophy 5 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 08, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	.;.;D;D;.;.;.;.;T
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.36	D
MetaRNN	Pathogenic	0.94	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.4	M;.;M;.;M;.;M;.;.
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-4.6	D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.96
Sift	Uncertain	0.0010	D;D;D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D;D;D;D
Polyphen		0.92	.;.;P;.;.;.;.;.;.
Vest4		0.91
MutPred		0.81		Gain of disorder (P = 0.0289);.;Gain of disorder (P = 0.0289);.;Gain of disorder (P = 0.0289);.;Gain of disorder (P = 0.0289);.;.;
MVP		0.97
MPC		2.4
ClinPred		0.99	D
GERP RS		5.1
Varity_R		0.90
gMVP		0.95

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: rs1555119216; hg19: chr12-32866261;