rs879255687

Positions:

• chr12-32708199-CAG-C

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PVS1 PP5

The NM_012062.5(DNM1L):​c.346_347delGA​(p.Glu116fs) 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 Conflicting classifications of pathogenicity (no stars). 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_012062.5 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1
• Conservation: PhyloP100: 5.42

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 9 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 [Conflicting_classifications_of_pathogenicity]. Clinvar id is 253264.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=2}. Variant chr12-32708199-CAG-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNM1L	NM_001278464.2	c.385_386delGA	p.Glu129fs	frameshift_variant	5/21	ENST00000553257.6	NP_001265393.1
DNM1L	NM_012062.5	c.346_347delGA	p.Glu116fs	frameshift_variant	4/20	ENST00000549701.6	NP_036192.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNM1L	ENST00000553257.6	c.385_386delGA	p.Glu129fs	frameshift_variant	5/21	2	NM_001278464.2	ENSP00000449089.1
DNM1L	ENST00000549701.6	c.346_347delGA	p.Glu116fs	frameshift_variant	4/20	1	NM_012062.5	ENSP00000450399.1

Frequencies

GnomAD3 genomes AF: 0.0000461 AC: 7 AN: 151822 Hom.: 0 Cov.: 32

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

GnomAD3 exomes AF: 0.0000441 AC: 11 AN: 249612 Hom.: 0 AF XY: 0.0000370 AC XY: 5 AN XY: 135272

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 SAS exome AF: 0.0000659

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000354

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000220 AC: 32 AN: 1451496 Hom.: 0 AF XY: 0.0000221 AC XY: 16 AN XY: 722662

Gnomad4 AFR exome AF: 0.0000301

Gnomad4 AMR exome AF: 0.0000449

Gnomad4 ASJ exome AF: 0.0000385

Gnomad4 EAS exome AF: 0.0000506

Gnomad4 SAS exome AF: 0.0000350

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.0000199

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000461 AC: 7 AN: 151822 Hom.: 0 Cov.: 32 AF XY: 0.0000674 AC XY: 5 AN XY: 74154

Gnomad4 AFR AF: 0.0000726

Gnomad4 AMR AF: 0.0000656

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000264

EpiCase AF: 0.0000546

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 02, 2023	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. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 20, 2024	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) -

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

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Oct 06, 2021	PVS1, PM2 -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 25, 2016	- -

Computational scores

Source: dbNSFP v4.3

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: rs879255687; hg19: chr12-32861133;