chr9-128218704-A-G

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_004408.4(DNM1):c.358A>G(p.Ile120Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000174 in 1,607,314 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

DNM1
NM_004408.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 9.32

Publications

0 publications found

Variant links:

Genes affected

DNM1 (HGNC:2972): (dynamin 1) This gene encodes a member of the dynamin subfamily of GTP-binding proteins. The encoded protein possesses unique mechanochemical properties used to tubulate and sever membranes, and is involved in clathrin-mediated endocytosis and other vesicular trafficking processes. Actin and other cytoskeletal proteins act as binding partners for the encoded protein, which can also self-assemble leading to stimulation of GTPase activity. More than sixty highly conserved copies of the 3' region of this gene are found elsewhere in the genome, particularly on chromosomes Y and 15. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Jul 2008]

DNM1 Gene-Disease associations (from GenCC):

genetic developmental and epileptic encephalopathy
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
developmental and epileptic encephalopathy, 31A
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
developmental and epileptic encephalopathy, 31B
Inheritance: AR, AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
Lennox-Gastaut syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
undetermined early-onset epileptic encephalopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

DNM1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNM1	NM_004408.4 link	c.358A>G	p.Ile120Val	missense_variant	Exon 3 of 22	ENST00000372923.8	NP_004399.2	Q05193-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNM1	ENST00000372923.8 link	c.358A>G	p.Ile120Val	missense_variant	Exon 3 of 22	1	NM_004408.4	ENSP00000362014.4		Q05193-1
DNM1	ENST00000634267.2 link	c.358A>G	p.Ile120Val	missense_variant	Exon 3 of 22	5		ENSP00000489096.1		A0A0U1RQP1

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

152042

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

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:

0.0000179

AC:

AN:

1455272

Hom.:

Cov.:

AF XY:

0.0000166

AC XY:

AN XY:

722616

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33350

American (AMR)

AF:

0.00

AC:

AN:

44422

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26026

East Asian (EAS)

AF:

0.0000253

AC:

AN:

39480

South Asian (SAS)

AF:

0.00

AC:

AN:

86004

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53084

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.0000226

AC:

AN:

1107116

Other (OTH)

AF:

0.00

AC:

AN:

60036

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000132

AC:

AN:

152042

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74258

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000242

AC:

AN:

41402

American (AMR)

AF:

0.00

AC:

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67982

Other (OTH)

AF:

0.00

AC:

AN:

2086

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.400

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

May 21, 2018

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

A variant of uncertain significance has been identified in the DNM1 gene. The I120V variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The I120V variant is observed in 1/8704 (0.01%) alleles from individuals of African background in large population cohorts (Lek et al., 2016). The I120V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -

Nov 07, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Developmental and epileptic encephalopathy, 31A

Uncertain:1

Feb 08, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 120 of the DNM1 protein (p.Ile120Val). This variant is present in population databases (no rsID available, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with DNM1-related conditions. ClinVar contains an entry for this variant (Variation ID: 377330). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on DNM1 protein function. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.57

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.19

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.77

D;.;.;.;.;.;T;.;.

Eigen

Pathogenic

0.83

Eigen_PC

Pathogenic

0.79

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.95

D;.;.;D;D;D;D;D;D

M_CAP

Pathogenic

0.54

MetaRNN

Uncertain

0.69

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

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.7

M;M;M;M;.;M;.;M;.

PhyloP100

9.3

PrimateAI

Uncertain

0.72

PROVEAN

Benign

-0.90

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

REVEL

Pathogenic

0.82

Sift

Uncertain

0.0010

D;D;D;D;.;D;.;.;.

Sift4G

Uncertain

0.0040

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

Polyphen

0.88

P;.;P;.;.;P;.;P;.

Vest4

0.62

MutPred

0.83

Loss of loop (P = 0.2237);Loss of loop (P = 0.2237);Loss of loop (P = 0.2237);Loss of loop (P = 0.2237);Loss of loop (P = 0.2237);Loss of loop (P = 0.2237);Loss of loop (P = 0.2237);Loss of loop (P = 0.2237);Loss of loop (P = 0.2237);

MVP

0.87

MPC

2.2

ClinPred

0.98

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.63

gMVP

0.75

Mutation Taster

=47/53

disease causing

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over