12-32679388-AACA-CACT

Position:

• chr12-32679388-AACA-CACT

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PVS1_Strong PM2 PP5

The NM_012062.5(DNM1L):​c.25_28delAACAinsCACT​(p.AsnLys9*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: DNM1L NM_012062.5 stop_gained
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 8.73

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 7 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 13 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-32679388-AACA-CACT is Pathogenic according to our data. Variant chr12-32679388-AACA-CACT is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 449012.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNM1L	NM_001278464.2	c.25_28delAACAinsCACT	p.AsnLys9*	stop_gained		ENST00000553257.6	NP_001265393.1
DNM1L	NM_012062.5	c.25_28delAACAinsCACT	p.AsnLys9*	stop_gained		ENST00000549701.6	NP_036192.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNM1L	ENST00000553257.6	c.25_28delAACAinsCACT	p.AsnLys9*	stop_gained		2	NM_001278464.2	ENSP00000449089.1
DNM1L	ENST00000549701.6	c.25_28delAACAinsCACT	p.AsnLys9*	stop_gained		1	NM_012062.5	ENSP00000450399.1

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 29, 2023	Nonsense indel 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; Has not been previously published as pathogenic or benign to our knowledge -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 25, 2019	- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Sep 26, 2023

Variant summary: DNM1L c.25_28delinsCACT (p.Asn9HisfsX2) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 2.5e-05 in 282020 control chromosomes (i.e., 7 heterozygotes; frequency represents the co-occurrence of constituent SNVs c.25A>C and c.28A>T; gnomAD v2.1.1). To our knowledge, no occurrence of c.25_28delinsCACT in individuals affected with Encephalopathy, Lethal, Due To Defective Mitochondrial Peroxisomal Fission 1, Autosomal Recessive and no experimental evidence demonstrating its impact on protein function have been reported. No occurrence of the constituent SNV c.25A>C (p.Asn9His) has been reported in isolation to our knowledge, although the second constituent SNV c.28A>T (p.Lys10X) has been reported in a heterozygous individual with extreme obesity and neuropsychiatric disease (e.g., Stahel_2019). The following publication was ascertained in the context of this evaluation (PMID: 31506345). Two submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. One submitter classified the variant as likely pathogenic, and one submitter classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1555229978; hg19: chr12-32832322;