12-32679370-G-A

Position:

chr12-32679370-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP2BP4

The NM_012062.5(DNM1L):c.7G>A(p.Ala3Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000124 in 1,612,932 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

DNM1L
NM_012062.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.34

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 links:

DNM1L (HGNC:):

DNM1L links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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 5.3198 (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.

BP4

Computational evidence support a benign effect (MetaRNN=0.36397457).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNM1L	NM_001278464.2 linkuse as main transcript	c.7G>A	p.Ala3Thr	missense_variant	1/21	ENST00000553257.6	NP_001265393.1	O00429-6B4DYR6
DNM1L	NM_012062.5 linkuse as main transcript	c.7G>A	p.Ala3Thr	missense_variant	1/20	ENST00000549701.6	NP_036192.2	O00429-1B4DYR6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNM1L	ENST00000553257.6 linkuse as main transcript	c.7G>A	p.Ala3Thr	missense_variant	1/21	2	NM_001278464.2	ENSP00000449089.1		O00429-6
DNM1L	ENST00000549701.6 linkuse as main transcript	c.7G>A	p.Ala3Thr	missense_variant	1/20	1	NM_012062.5	ENSP00000450399.1		O00429-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460718

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726768

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.00e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152214

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74362

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 20, 2023

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬† is likely to be tolerated. This variant has not been reported in the literature in individuals affected with DNM1L-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 3 of the DNM1L protein (p.Ala3Thr). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.43

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Uncertain

-0.030

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.34

.;.;T;T;.;T;.;.;.;T

Eigen

Benign

-0.14

Eigen_PC

Benign

0.044

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.93

D;D;D;D;D;D;D;D;D;D

M_CAP

Pathogenic

0.61

MetaRNN

Benign

0.36

T;T;T;T;T;T;T;T;T;T

MetaSVM

Uncertain

0.19

MutationAssessor

Benign

0.11

N;N;N;.;N;.;.;N;N;.

PrimateAI

Pathogenic

0.80

PROVEAN

Benign

-1.5

N;N;N;N;N;N;N;N;N;N

REVEL

Uncertain

0.33

Sift

Benign

0.56

T;T;T;T;T;T;T;T;T;T

Sift4G

Benign

0.40

T;T;T;T;T;T;T;T;T;T

Polyphen

0.048

.;.;B;.;.;.;.;.;.;.

Vest4

0.26

MutPred

0.31

Gain of catalytic residue at I5 (P = 0.0013);Gain of catalytic residue at I5 (P = 0.0013);Gain of catalytic residue at I5 (P = 0.0013);Gain of catalytic residue at I5 (P = 0.0013);Gain of catalytic residue at I5 (P = 0.0013);Gain of catalytic residue at I5 (P = 0.0013);Gain of catalytic residue at I5 (P = 0.0013);Gain of catalytic residue at I5 (P = 0.0013);Gain of catalytic residue at I5 (P = 0.0013);Gain of catalytic residue at I5 (P = 0.0013);

MVP

0.92

MPC

1.1

ClinPred

0.73

GERP RS

3.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.51

gMVP

0.37

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

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over