dbSNP rs3003609: DNM1:p.Phe336Phe (chr9-128222476-C-T) – ACMG Classification: Benign (-19 pts)

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_004408.4(DNM1):c.1008C>T(p.Phe336Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.532 in 1,613,764 control chromosomes in the GnomAD database, including 236,688 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.43 ( 17223 hom., cov: 32)

Exomes 𝑓: 0.54 ( 219465 hom. )

Consequence

DNM1
NM_004408.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.579

Publications

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

DNM1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.3).

BP6

Variant 9-128222476-C-T is Benign according to our data. Variant chr9-128222476-C-T is described in ClinVar as Benign. ClinVar VariationId is 380777.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.579 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.592 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	UniProt
DNM1	NM_004408.4	MANE Select	c.1008C>T	p.Phe336Phe	synonymous	Exon 8 of 22	NP_004399.2	Q05193-1
DNM1	NM_001374269.1		c.1008C>T	p.Phe336Phe	synonymous	Exon 8 of 22	NP_001361198.1	A0A994J7J4
DNM1	NM_001288739.2		c.1008C>T	p.Phe336Phe	synonymous	Exon 8 of 22	NP_001275668.1	Q05193-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DNM1	ENST00000372923.8	TSL:1 MANE Select	c.1008C>T	p.Phe336Phe	synonymous	Exon 8 of 22	ENSP00000362014.4	Q05193-1
DNM1	ENST00000486160.3	TSL:1	c.1008C>T	p.Phe336Phe	synonymous	Exon 8 of 22	ENSP00000420045.1	Q05193-2
DNM1	ENST00000634267.2	TSL:5	c.1008C>T	p.Phe336Phe	synonymous	Exon 8 of 22	ENSP00000489096.1	A0A0U1RQP1

Frequencies

GnomAD3 genomes

AF:

0.433

AC:

65773

AN:

151902

Hom.:

17215

Cov.:

show subpopulations

Gnomad AFR

AF:

0.122

Gnomad AMI

AF:

0.659

Gnomad AMR

AF:

0.602

Gnomad ASJ

AF:

0.447

Gnomad EAS

AF:

0.588

Gnomad SAS

AF:

0.590

Gnomad FIN

AF:

0.531

Gnomad MID

AF:

0.468

Gnomad NFE

AF:

0.542

Gnomad OTH

AF:

0.465

GnomAD2 exomes

AF:

0.542

AC:

136150

AN:

251218

AF XY:

0.546

show subpopulations

Gnomad AFR exome

AF:

0.115

Gnomad AMR exome

AF:

0.707

Gnomad ASJ exome

AF:

0.443

Gnomad EAS exome

AF:

0.599

Gnomad FIN exome

AF:

0.534

Gnomad NFE exome

AF:

0.543

Gnomad OTH exome

AF:

0.542

GnomAD4 exome

AF:

0.542

AC:

792635

AN:

1461744

Hom.:

219465

Cov.:

AF XY:

0.543

AC XY:

394906

AN XY:

727172

show subpopulations

African (AFR)

AF:

0.104

AC:

3472

AN:

33476

American (AMR)

AF:

0.692

AC:

30922

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.439

AC:

11466

AN:

26130

East Asian (EAS)

AF:

0.581

AC:

23062

AN:

39698

South Asian (SAS)

AF:

0.581

AC:

50154

AN:

86254

European-Finnish (FIN)

AF:

0.541

AC:

28894

AN:

53392

Middle Eastern (MID)

AF:

0.478

AC:

2759

AN:

5768

European-Non Finnish (NFE)

AF:

0.549

AC:

610119

AN:

1111924

Other (OTH)

AF:

0.526

AC:

31787

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

20509

41018

61528

82037

102546

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

17140

34280

51420

68560

85700

<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:

0.433

AC:

65779

AN:

152020

Hom.:

17223

Cov.:

AF XY:

0.439

AC XY:

32590

AN XY:

74278

show subpopulations

African (AFR)

AF:

0.122

AC:

5055

AN:

41506

American (AMR)

AF:

0.602

AC:

9193

AN:

15264

Ashkenazi Jewish (ASJ)

AF:

0.447

AC:

1553

AN:

3472

East Asian (EAS)

AF:

0.588

AC:

3031

AN:

5152

South Asian (SAS)

AF:

0.589

AC:

2833

AN:

4810

European-Finnish (FIN)

AF:

0.531

AC:

5611

AN:

10572

Middle Eastern (MID)

AF:

0.469

AC:

138

AN:

294

European-Non Finnish (NFE)

AF:

0.541

AC:

36782

AN:

67928

Other (OTH)

AF:

0.465

AC:

982

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1678

3357

5035

6714

8392

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

608

1216

1824

2432

3040

<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:

0.510

Hom.:

98459

Bravo

AF:

0.424

Asia WGS

AF:

0.570

AC:

1978

AN:

3478

EpiCase

AF:

0.540

EpiControl

AF:

0.543

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Developmental and epileptic encephalopathy, 31A (2)

not provided (2)

not specified (2)

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.30

CADD

Benign

7.0

(source)

DANN

Benign

0.87

PhyloP100

0.58

Mutation Taster

=98/2

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

Computational scores

Splicing

Publications

Other links and lift over