12-32713327-C-A

Variant names:

• chr12-32713327-C-A
• rs1555119216
• NM_001278464.2:c.614C>A

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PP2 PP3_Strong PP5

The NM_001278464.2(DNM1L):​c.614C>A​(p.Ala205Glu) 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_001278464.2 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.64
• Publications: 2 publications found

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 Gene-Disease associations (from GenCC):

• encephalopathy due to mitochondrial and peroxisomal fission defect

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• encephalopathy, lethal, due to defective mitochondrial peroxisomal fission 1

  Inheritance: AD, AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• optic atrophy 5

  Inheritance: AD Classification: STRONG Submitted by: G2P
• autosomal dominant optic atrophy, classic form

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Leigh syndrome

  Inheritance: AR, AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• 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, optic atrophy 5, autosomal dominant optic atrophy, classic form, Leigh syndrome, encephalopathy due to mitochondrial and peroxisomal fission defect.
• 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 VariationId is 446170.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001278464.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNM1L	NM_001278464.2	MANE Plus Clinical	c.614C>A	p.Ala205Glu	missense	Exon 7 of 21	NP_001265393.1
	DNM1L	NM_012062.5	MANE Select	c.575C>A	p.Ala192Glu	missense	Exon 6 of 20	NP_036192.2
	DNM1L	NM_001278465.2		c.614C>A	p.Ala205Glu	missense	Exon 7 of 20	NP_001265394.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNM1L	ENST00000553257.6	TSL:2 MANE Plus Clinical	c.614C>A	p.Ala205Glu	missense	Exon 7 of 21	ENSP00000449089.1
	DNM1L	ENST00000549701.6	TSL:1 MANE Select	c.575C>A	p.Ala192Glu	missense	Exon 6 of 20	ENSP00000450399.1
	DNM1L	ENST00000381000.8	TSL:1	c.614C>A	p.Ala205Glu	missense	Exon 7 of 20	ENSP00000370388.4

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

Nov 08, 2017

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

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
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.36	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		7.6
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-4.6	D
REVEL	Pathogenic	0.96
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.92	P
Vest4		0.91
MutPred		0.81		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
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1555119216; hg19: chr12-32866261;