chr12-32731018-G-A

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2PM5PP2PP3_ModeratePP5_Very_Strong

The NM_012062.5(DNM1L):​c.1084G>A​(p.Gly362Ser) 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. G362D) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 33)

Consequence

DNM1L
NM_012062.5 missense

Scores

16
2
1

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 9.74
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]
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 17 ACMG points.

PM1
In a region_of_interest Middle domain (size 145) in uniprot entity DNM1L_HUMAN there are 10 pathogenic changes around while only 1 benign (91%) in NM_012062.5
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 Lovd as [Pathogenic].
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: 5.3198 (above the threshold of 3.09). GenCC associations: The gene is linked to 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 rank MANE Protein UniProt
DNM1LNM_001278464.2 linkc.1123G>A p.Gly375Ser missense_variant Exon 11 of 21 ENST00000553257.6 NP_001265393.1 O00429-6B4DYR6
DNM1LNM_012062.5 linkc.1084G>A p.Gly362Ser missense_variant Exon 10 of 20 ENST00000549701.6 NP_036192.2 O00429-1B4DYR6

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
DNM1LENST00000553257.6 linkc.1123G>A p.Gly375Ser missense_variant Exon 11 of 21 2 NM_001278464.2 ENSP00000449089.1 O00429-6
DNM1LENST00000549701.6 linkc.1084G>A p.Gly362Ser missense_variant Exon 10 of 20 1 NM_012062.5 ENSP00000450399.1 O00429-1

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
LINK: link

Submissions by phenotype

Encephalopathy, lethal, due to defective mitochondrial peroxisomal fission 1 Pathogenic:3
-
Suma Genomics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Aug 25, 2016
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Aug 27, 2018
Baylor Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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]. -

not provided Pathogenic:2
Apr 12, 2022
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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) -

Mar 24, 2021
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. 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. -

DNM1L-related disorder Pathogenic:1
Dec 01, 2023
PreventionGenetics, part of Exact Sciences
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

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;.
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs886037861; hg19: chr12-32883952; API