9-128203516-C-A

Variant names:

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

The NM_004408.4(DNM1):c.46C>A(p.Leu16Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00753 in 1,540,792 control chromosomes in the GnomAD database, including 292 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0070 ( 36 hom., cov: 31)

Exomes 𝑓: 0.0076 ( 256 hom. )

Consequence

DNM1
NM_004408.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 1.54

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 links:

CIZ1 (HGNC:16744): (CDKN1A interacting zinc finger protein 1) The protein encoded by this gene is a zinc finger DNA binding protein that interacts with CIP1, part of a complex with cyclin E. The encoded protein may regulate the cellular localization of CIP1. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2012]

CIZ1 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

PP2

Missense variant in the DNM1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 39 curated pathogenic missense variants (we use a threshold of 10). The gene has 46 curated benign missense variants. Gene score misZ: 5.1795 (above the threshold of 3.09). Trascript score misZ: 5.021 (above the threshold of 3.09). GenCC associations: The gene is linked to developmental and epileptic encephalopathy, 31, undetermined early-onset epileptic encephalopathy, developmental and epileptic encephalopathy 31B, developmental and epileptic encephalopathy, Lennox-Gastaut syndrome.

BP4

Computational evidence support a benign effect (MetaRNN=0.0020967126).

BP6

Variant 9-128203516-C-A is Benign according to our data. Variant chr9-128203516-C-A is described in ClinVar as [Benign]. Clinvar id is 380950.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0917 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNM1	NM_004408.4 link	c.46C>A	p.Leu16Met	missense_variant	Exon 1 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.46C>A	p.Leu16Met	missense_variant	Exon 1 of 22	1	NM_004408.4	ENSP00000362014.4		Q05193-1
DNM1	ENST00000634267.2 link	c.46C>A	p.Leu16Met	missense_variant	Exon 1 of 22	5		ENSP00000489096.1		A0A0U1RQP1

Frequencies

GnomAD3 genomes

AF:

0.00705

AC:

1071

AN:

151860

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00106

Gnomad AMI

AF:

0.0286

Gnomad AMR

AF:

0.00544

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0992

Gnomad SAS

AF:

0.0271

Gnomad FIN

AF:

0.000668

Gnomad MID

AF:

0.00318

Gnomad NFE

AF:

0.00374

Gnomad OTH

AF:

0.00575

GnomAD3 exomes

AF:

0.0138

AC:

2346

AN:

170580

Hom.:

AF XY:

0.0135

AC XY:

1283

AN XY:

95134

show subpopulations

Gnomad AFR exome

AF:

0.00181

Gnomad AMR exome

AF:

0.0163

Gnomad ASJ exome

AF:

0.000256

Gnomad EAS exome

AF:

0.0947

Gnomad SAS exome

AF:

0.0272

Gnomad FIN exome

AF:

0.000923

Gnomad NFE exome

AF:

0.00501

Gnomad OTH exome

AF:

0.00814

GnomAD4 exome

AF:

0.00758

AC:

10530

AN:

1388824

Hom.:

256

Cov.:

AF XY:

0.00808

AC XY:

5572

AN XY:

689566

show subpopulations

Gnomad4 AFR exome

AF:

0.000942

Gnomad4 AMR exome

AF:

0.0131

Gnomad4 ASJ exome

AF:

0.000375

Gnomad4 EAS exome

AF:

0.105

Gnomad4 SAS exome

AF:

0.0273

Gnomad4 FIN exome

AF:

0.00110

Gnomad4 NFE exome

AF:

0.00378

Gnomad4 OTH exome

AF:

0.00764

GnomAD4 genome

AF:

0.00703

AC:

1068

AN:

151968

Hom.:

Cov.:

AF XY:

0.00808

AC XY:

600

AN XY:

74284

show subpopulations

Gnomad4 AFR

AF:

0.00106

Gnomad4 AMR

AF:

0.00543

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0988

Gnomad4 SAS

AF:

0.0271

Gnomad4 FIN

AF:

0.000668

Gnomad4 NFE

AF:

0.00374

Gnomad4 OTH

AF:

0.00617

Alfa

AF:

0.00776

Hom.:

Bravo

AF:

0.00771

ESP6500AA

AF:

0.00137

AC:

ESP6500EA

AF:

0.00316

AC:

ExAC

AF:

0.0143

AC:

1720

Asia WGS

AF:

0.0420

AC:

141

AN:

3388

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Developmental and epileptic encephalopathy, 31A

Benign:2

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 18, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Sep 14, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:1

Jan 22, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Inborn genetic diseases

Benign:1

Feb 22, 2016

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Uncertain

-0.070

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Uncertain

0.53

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

Eigen

Benign

-0.22

Eigen_PC

Benign

-0.22

FATHMM_MKL

Benign

0.75

LIST_S2

Uncertain

0.93

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

MetaRNN

Benign

0.0021

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

MetaSVM

Benign

-0.36

MutationAssessor

Uncertain

2.7

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

PrimateAI

Pathogenic

0.85

PROVEAN

Benign

-1.6

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

REVEL

Uncertain

0.52

Sift

Uncertain

0.019

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

Sift4G

Uncertain

0.029

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

Polyphen

0.012

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

Vest4

0.093

MPC

1.8

ClinPred

0.029

GERP RS

1.9

Varity_R

0.27

gMVP

0.76

Splicing

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