NM_001278464.2:c.385_386delGA

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_001278464.2(DNM1L):c.385_386delGA(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 Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000022 ( 0 hom. )

Consequence

DNM1L
NM_001278464.2 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 5.42

Publications

11 publications found

Variant links:

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

DNM1L links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 16 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 253264.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNM1L	NM_001278464.2 link	c.385_386delGA	p.Glu129LysfsTer6	frameshift_variant	Exon 5 of 21	ENST00000553257.6	NP_001265393.1
DNM1L	NM_012062.5 link	c.346_347delGA	p.Glu116LysfsTer6	frameshift_variant	Exon 4 of 20	ENST00000549701.6	NP_036192.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNM1L	ENST00000553257.6 link	c.385_386delGA	p.Glu129LysfsTer6	frameshift_variant	Exon 5 of 21	2	NM_001278464.2	ENSP00000449089.1
DNM1L	ENST00000549701.6 link	c.346_347delGA	p.Glu116LysfsTer6	frameshift_variant	Exon 4 of 20	1	NM_012062.5	ENSP00000450399.1

Frequencies

GnomAD3 genomes

AF:

0.0000461

AC:

AN:

151822

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000726

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000656

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000441

AC:

AN:

249612

AF XY:

0.0000370

show subpopulations

Gnomad AFR exome

AF:

0.0000638

Gnomad AMR exome

AF:

0.0000872

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000354

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000220

AC:

AN:

1451496

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

722662

show subpopulations

African (AFR)

AF:

0.0000301

AC:

AN:

33254

American (AMR)

AF:

0.0000449

AC:

AN:

44554

Ashkenazi Jewish (ASJ)

AF:

0.0000385

AC:

AN:

25990

East Asian (EAS)

AF:

0.0000506

AC:

AN:

39496

South Asian (SAS)

AF:

0.0000350

AC:

AN:

85780

European-Finnish (FIN)

AF:

0.0000188

AC:

AN:

53302

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5722

European-Non Finnish (NFE)

AF:

0.0000199

AC:

AN:

1103338

Other (OTH)

AF:

0.00

AC:

AN:

60060

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.442

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000461

AC:

AN:

151822

Hom.:

Cov.:

AF XY:

0.0000674

AC XY:

AN XY:

74154

show subpopulations

African (AFR)

AF:

0.0000726

AC:

AN:

41300

American (AMR)

AF:

0.0000656

AC:

AN:

15246

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5196

South Asian (SAS)

AF:

0.000207

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10504

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

67962

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000264

EpiCase

AF:

0.0000546

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Encephalopathy, lethal, due to defective mitochondrial peroxisomal fission 1

Pathogenic:2

Aug 25, 2016

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Oct 06, 2021

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PVS1, PM2 Loss-of-function variants in DNM1L are known to be pathogenic (PMID: 26825290, 27328748). This variant is associated with the following publications: (PMID: 26825290, 33742459). It was inherited by unaffected mother, reduced penetrance has been reported. -

not provided

Pathogenic:2

Mar 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Feb 20, 2024

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

5.4

Mutation Taster

=0/200

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over