12-32731018-G-A

Position:

• chr12-32731018-G-A

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5_Very_Strong

The NM_001278464.2(DNM1L):​c.1123G>A​(p.Gly375Ser) 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. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G375D) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: DNM1L NM_001278464.2 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 9.74

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]

YARS2 (HGNC:24249): (tyrosyl-tRNA synthetase 2) This gene encodes a mitochondrial protein that catalyzes the attachment of tyrosine to tRNA(Tyr). Mutations in this gene are associated with myopathy with lactic acidosis and sideroblastic anemia type 2 (MLASA2). [provided by RefSeq, Jan 2011]

ACMG classification

Verdict is Pathogenic. Variant got 17 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_001278464.2
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-32731019-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 253261.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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 5.2186 (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, 0.918
• PP5: Variant 12-32731018-G-A is Pathogenic according to our data. Variant chr12-32731018-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 253262.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-32731018-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNM1L	NM_001278464.2	c.1123G>A	p.Gly375Ser	missense_variant	11/21	ENST00000553257.6
DNM1L	NM_012062.5	c.1084G>A	p.Gly362Ser	missense_variant	10/20	ENST00000549701.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNM1L	ENST00000553257.6	c.1123G>A	p.Gly375Ser	missense_variant	11/21	2	NM_001278464.2
DNM1L	ENST00000549701.6	c.1084G>A	p.Gly362Ser	missense_variant	10/20	1	NM_012062.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Encephalopathy, lethal, due to defective mitochondrial peroxisomal fission 1 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Aug 27, 2018	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant was previously reported to occur de novo in a patient with neonatal cyanosis and respiratory distress, postnatal microcephaly, developmental delay with scanty spontaneous movement, hypotonia, and pain insensitivity [PMID 26992161]. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 25, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Suma Genomics, Suma Genomics	-	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Mar 24, 2021	Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. Experimental studies have shown that this variant affects DNM1L protein function (PMID: 30801875). This variant has been observed in individual(s) with DNM1L-related conditions (PMID: 26992161, 30801875, 31475481). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 253262). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with serine at codon 362 of the DNM1L protein (p.Gly362Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 12, 2022	Published functional studies demonstrate a dominant negative effect as this variant significantly impaired oxidative growth and reduced respiratory activity (Verrigni et al., 2019); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 30801875, 31475481, 32005694, 31785789, 26992161) -

DNM1L-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 01, 2023

The DNM1L c.1084G>A variant is predicted to result in the amino acid substitution p.Gly362Ser. This variant was reported to have occurred de novo in multiple individuals with DNM1L-related phenotypes (Sheffer et al. 2016. PubMed ID: 26992161; Verrigni et al. 2019. PubMed ID: 30801875; Table S2, Turner et al. 2019. PubMed ID: 31785789; Table S2, Dong et al. 2020. PubMed ID: 32005694). Functional studies showed that this variant impacts protein function (described as p.Gly397Ser in Saccharomyces cerevisiae studies, Verrigni et al. 2019. PubMed ID: 30801875). This variant has not been reported in a large population database, indicating this variant is rare. A different nucleotide substitution affecting the same amino acid (p.Gly362Asp) has also been reported in individuals with DNM1L-related phenotypes (Verrigni et al. 2019. PubMed ID: 30801875; Table S1, Bruel et al. 2019. PubMed ID: 31231135). Taken together, the c.1084G>A (p.Gly362Ser) variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	.;.;.;D;D;.;.;.
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.34	D
MetaRNN	Pathogenic	0.92	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.80	D
MutationAssessor	Pathogenic	3.8	H;.;.;H;.;H;H;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-5.5	D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.88
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D;D;D;D;D
Polyphen		1.0	.;.;.;D;.;.;.;.
Vest4		0.89
MutPred		0.79		Gain of catalytic residue at R365 (P = 0);.;.;Gain of catalytic residue at R365 (P = 0);.;Gain of catalytic residue at R365 (P = 0);Gain of catalytic residue at R365 (P = 0);.;
MVP		0.96
MPC		2.3
ClinPred		1.0	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.96
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs886037861; hg19: chr12-32883952;