Genetic Variant DNM3:p.Arg228Cys (chr1-172032494-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_015569.5(DNM3):c.682C>T(p.Arg228Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000556 in 1,474,234 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R228H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00025 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000035 ( 0 hom. )

Consequence

DNM3
NM_015569.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.10

Publications

5 publications found

Variant links:

Genes affected

DNM3 (HGNC:29125): (dynamin 3) This gene encodes a member of a family of guanosine triphosphate (GTP)-binding proteins that associate with microtubules and are involved in vesicular transport. The encoded protein functions in the development of megakaryocytes. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2013]

DNM3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.895

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015569.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DNM3	NM_015569.5	MANE Select	c.682C>T	p.Arg228Cys	missense	Exon 5 of 21	NP_056384.2
DNM3	NM_001350204.2		c.682C>T	p.Arg228Cys	missense	Exon 5 of 21	NP_001337133.1	Q9UQ16-1
DNM3	NM_001136127.3		c.682C>T	p.Arg228Cys	missense	Exon 5 of 20	NP_001129599.1	Q9UQ16-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DNM3	ENST00000627582.3	TSL:1 MANE Select	c.682C>T	p.Arg228Cys	missense	Exon 5 of 21	ENSP00000486701.1	Q9UQ16-3
DNM3	ENST00000367731.5	TSL:1	c.682C>T	p.Arg228Cys	missense	Exon 5 of 20	ENSP00000356705.1	Q9UQ16-2
DNM3	ENST00000485254.3	TSL:1	c.682C>T	p.Arg228Cys	missense	Exon 5 of 21	ENSP00000429165.2	H0YBC6

Frequencies

GnomAD3 genomes

AF:

0.000249

AC:

AN:

140418

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000686

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000510

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:

0.0000152

Gnomad OTH

AF:

0.000524

GnomAD2 exomes

AF:

0.0000445

AC:

AN:

247260

AF XY:

0.0000373

show subpopulations

Gnomad AFR exome

AF:

0.000521

Gnomad AMR exome

AF:

0.0000295

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000178

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000352

AC:

AN:

1333816

Hom.:

Cov.:

AF XY:

0.0000315

AC XY:

AN XY:

667660

show subpopulations

African (AFR)

AF:

0.000790

AC:

AN:

31638

American (AMR)

AF:

0.0000457

AC:

AN:

43770

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24184

East Asian (EAS)

AF:

0.00

AC:

AN:

37864

South Asian (SAS)

AF:

0.00

AC:

AN:

83742

European-Finnish (FIN)

AF:

0.0000392

AC:

AN:

51056

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5252

European-Non Finnish (NFE)

AF:

0.0000150

AC:

AN:

1001270

Other (OTH)

AF:

0.0000545

AC:

AN:

55040

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

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:

0.000249

AC:

AN:

140418

Hom.:

Cov.:

AF XY:

0.000223

AC XY:

AN XY:

67318

show subpopulations

African (AFR)

AF:

0.000686

AC:

AN:

37886

American (AMR)

AF:

0.000510

AC:

AN:

13730

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3376

East Asian (EAS)

AF:

0.00

AC:

AN:

4776

South Asian (SAS)

AF:

0.00

AC:

AN:

4296

European-Finnish (FIN)

AF:

0.00

AC:

AN:

7648

Middle Eastern (MID)

AF:

0.00

AC:

AN:

248

European-Non Finnish (NFE)

AF:

0.0000152

AC:

AN:

65666

Other (OTH)

AF:

0.000524

AC:

AN:

1908

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

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:

0.00364

Hom.:

Bravo

AF:

0.000238

ESP6500AA

AF:

0.00135

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000579

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.79

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Pathogenic

0.32

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.95

Eigen

Pathogenic

0.99

Eigen_PC

Pathogenic

0.92

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

1.0

M_CAP

Uncertain

0.28

MetaRNN

Pathogenic

0.90

MetaSVM

Uncertain

0.56

MutationAssessor

Pathogenic

3.6

PhyloP100

6.1

PrimateAI

Pathogenic

0.79

PROVEAN

Pathogenic

-7.7

REVEL

Pathogenic

0.83

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.78

MVP

0.97

ClinPred

1.0

GERP RS

5.8

Varity_R

0.87

gMVP

0.81

Mutation Taster

=66/34

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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