rs61757224

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_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

Publications

6 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 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 Gene-Disease associations (from GenCC):

dystonia 23
Inheritance: Unknown Classification: MODERATE Submitted by: Genomics England PanelApp
inherited dystonia
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

CIZ1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004408.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
DNM1	NM_004408.4	MANE Select	c.46C>A	p.Leu16Met	missense	Exon 1 of 22	NP_004399.2
DNM1	NM_001374269.1		c.46C>A	p.Leu16Met	missense	Exon 1 of 22	NP_001361198.1
DNM1	NM_001288739.2		c.46C>A	p.Leu16Met	missense	Exon 1 of 22	NP_001275668.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
DNM1	ENST00000372923.8	TSL:1 MANE Select	c.46C>A	p.Leu16Met	missense	Exon 1 of 22	ENSP00000362014.4
DNM1	ENST00000486160.3	TSL:1	c.46C>A	p.Leu16Met	missense	Exon 1 of 22	ENSP00000420045.1
DNM1	ENST00000634267.2	TSL:5	c.46C>A	p.Leu16Met	missense	Exon 1 of 22	ENSP00000489096.1

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

GnomAD2 exomes

AF:

0.0138

AC:

2346

AN:

170580

AF XY:

0.0135

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 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

African (AFR)

AF:

0.000942

AC:

AN:

28658

American (AMR)

AF:

0.0131

AC:

463

AN:

35404

Ashkenazi Jewish (ASJ)

AF:

0.000375

AC:

AN:

24004

East Asian (EAS)

AF:

0.105

AC:

3301

AN:

31524

South Asian (SAS)

AF:

0.0273

AC:

2148

AN:

78720

European-Finnish (FIN)

AF:

0.00110

AC:

AN:

48892

Middle Eastern (MID)

AF:

0.00306

AC:

AN:

5562

European-Non Finnish (NFE)

AF:

0.00378

AC:

4076

AN:

1079118

Other (OTH)

AF:

0.00764

AC:

435

AN:

56942

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

526

1053

1579

2106

2632

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

212

424

636

848

1060

<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:

0.00703

AC:

1068

AN:

151968

Hom.:

Cov.:

AF XY:

0.00808

AC XY:

600

AN XY:

74284

show subpopulations

African (AFR)

AF:

0.00106

AC:

AN:

41542

American (AMR)

AF:

0.00543

AC:

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.0988

AC:

509

AN:

5154

South Asian (SAS)

AF:

0.0271

AC:

131

AN:

4834

European-Finnish (FIN)

AF:

0.000668

AC:

AN:

10478

Middle Eastern (MID)

AF:

0.00342

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00374

AC:

254

AN:

67906

Other (OTH)

AF:

0.00617

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

148

197

246

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00736

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

Sep 14, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

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 v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Uncertain

-0.070

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Uncertain

0.53

Eigen

Benign

-0.22

Eigen_PC

Benign

-0.22

FATHMM_MKL

Benign

0.75

LIST_S2

Uncertain

0.93

MetaRNN

Benign

0.0021

MetaSVM

Benign

-0.36

MutationAssessor

Uncertain

2.7

PhyloP100

1.5

PrimateAI

Pathogenic

0.85

PROVEAN

Benign

-1.6

REVEL

Uncertain

0.52

Sift

Uncertain

0.019

Sift4G

Uncertain

0.029

Polyphen

0.012

Vest4

0.093

MPC

1.8

ClinPred

0.029

GERP RS

1.9

PromoterAI

0.31

Neutral

(source)

Varity_R

0.27

gMVP

0.76

Mutation Taster

=100/0

polymorphism (auto)

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over