chr9-128254659-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_004408.4(DNM1):c.2540C>T(p.Ser847Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000264 in 1,596,020 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. S847S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00068 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00022 ( 3 hom. )

Consequence

DNM1
NM_004408.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 5.69

Publications

1 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: Benign. The variant received -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0076565444).

BP6

Variant 9-128254659-C-T is Benign according to our data. Variant chr9-128254659-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 377087.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAdExome4 at 3 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNM1	NM_004408.4 link	c.2540C>T	p.Ser847Leu	missense_variant	Exon 22 of 22	ENST00000372923.8	NP_004399.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNM1	ENST00000372923.8 link	c.2540C>T	p.Ser847Leu	missense_variant	Exon 22 of 22	1	NM_004408.4	ENSP00000362014.4
DNM1	ENST00000634267.2 link	c.2544C>T	p.Ile848Ile	synonymous_variant	Exon 22 of 22	5		ENSP00000489096.1

Frequencies

GnomAD3 genomes

AF:

0.000677

AC:

103

AN:

152068

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:

0.00886

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000479

AC:

112

AN:

233586

AF XY:

0.000483

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00765

Gnomad NFE exome

AF:

0.000184

Gnomad OTH exome

AF:

0.000336

GnomAD4 exome

AF:

0.000220

AC:

318

AN:

1443952

Hom.:

Cov.:

AF XY:

0.000225

AC XY:

162

AN XY:

718718

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33396

American (AMR)

AF:

0.00

AC:

AN:

44692

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26126

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39686

South Asian (SAS)

AF:

0.00

AC:

AN:

86154

European-Finnish (FIN)

AF:

0.00684

AC:

260

AN:

38028

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4132

European-Non Finnish (NFE)

AF:

0.0000360

AC:

AN:

1111642

Other (OTH)

AF:

0.000266

AC:

AN:

60096

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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:

0.000677

AC:

103

AN:

152068

Hom.:

Cov.:

AF XY:

0.00105

AC XY:

AN XY:

74270

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41380

American (AMR)

AF:

0.00

AC:

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00886

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000132

AC:

AN:

68022

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.000424

Hom.:

Bravo

AF:

0.0000416

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000214

AC:

ExAC

AF:

0.000633

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Developmental and epileptic encephalopathy, 31A

Benign:1

Apr 10, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Sep 02, 2016

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

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Uncertain

-0.070

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.25

T;.;T

Eigen

Benign

-0.040

Eigen_PC

Benign

0.17

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.78

T;T;T

M_CAP

Benign

0.022

MetaRNN

Benign

0.0077

T;T;T

MetaSVM

Benign

-0.45

MutationAssessor

Benign

0.34

N;N;.

PhyloP100

5.7

PrimateAI

Uncertain

0.70

PROVEAN

Benign

-0.62

N;N;.

REVEL

Benign

0.25

Sift

Benign

0.21

T;T;.

Sift4G

Benign

0.31

T;T;T

Polyphen

0.043

B;.;.

Vest4

0.16

MVP

0.69

MPC

1.1

ClinPred

0.055

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.15

gMVP

0.076

Mutation Taster

=97/3

polymorphism

(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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over