Genetic Variant DNMBP:c.2261-20486G>A (chr10-99929632-C-T) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

The NM_001318326.2(DNMBP):c.1132G>A(p.Val378Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0172 in 687,158 control chromosomes in the GnomAD database, including 187 homozygotes. In-silico tool predicts a benign outcome for this variant. 8/9 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.013 ( 24 hom., cov: 32)

Exomes 𝑓: 0.018 ( 163 hom. )

Consequence

DNMBP
NM_001318326.2 missense

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: 2.13

Publications

3 publications found

Variant links:

Genes affected

DNMBP (HGNC:30373): (dynamin binding protein) This gene encodes a protein belonging to the guanine nucleotide exchange factor family, and which regulates the configuration of cell junctions. It contains multiple binding sites for dynamin and thus links dynamin to actin regulatory proteins. Polymorphisms in this gene have been linked to Alzheimer's disease in some populations, though there are conflicting reports of such linkages in other populations. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2015]

DNMBP links:

DNMBP-AS1 (HGNC:20431): (DNMBP antisense RNA 1)

DNMBP-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0038205087).

BP6

Variant 10-99929632-C-T is Benign according to our data. Variant chr10-99929632-C-T is described in ClinVar as Benign. ClinVar VariationId is 3041475.Status of the report is no_assertion_criteria_provided, 0 stars.

BA1

GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.061 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001318326.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DNMBP	NM_015221.4	MANE Select	c.2261-20486G>A		intron	N/A	NP_056036.1	Q6XZF7-1
DNMBP	NM_001318326.2		c.1132G>A	p.Val378Met	missense	Exon 1 of 14	NP_001305255.1	A0A1B0GTX1
DNMBP	NM_001441287.1		c.2261-20486G>A		intron	N/A	NP_001428216.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DNMBP	ENST00000324109.9	TSL:1 MANE Select	c.2261-20486G>A		intron	N/A	ENSP00000315659.4	Q6XZF7-1
DNMBP	ENST00000636706.1	TSL:2	c.1132G>A	p.Val378Met	missense	Exon 1 of 14	ENSP00000489875.1	A0A1B0GTX1
DNMBP	ENST00000856964.1		c.2261-20486G>A		intron	N/A	ENSP00000527023.1

Frequencies

GnomAD3 genomes

AF:

0.0131

AC:

1993

AN:

152140

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00292

Gnomad AMI

AF:

0.0976

Gnomad AMR

AF:

0.0131

Gnomad ASJ

AF:

0.0357

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0352

Gnomad FIN

AF:

0.00358

Gnomad MID

AF:

0.0601

Gnomad NFE

AF:

0.0175

Gnomad OTH

AF:

0.0192

GnomAD2 exomes

AF:

0.0179

AC:

2136

AN:

119556

AF XY:

0.0195

show subpopulations

Gnomad AFR exome

AF:

0.00225

Gnomad AMR exome

AF:

0.0125

Gnomad ASJ exome

AF:

0.0320

Gnomad EAS exome

AF:

0.000304

Gnomad FIN exome

AF:

0.00446

Gnomad NFE exome

AF:

0.0181

Gnomad OTH exome

AF:

0.0285

GnomAD4 exome

AF:

0.0184

AC:

9846

AN:

534900

Hom.:

163

Cov.:

AF XY:

0.0195

AC XY:

5649

AN XY:

289778

show subpopulations

African (AFR)

AF:

0.00331

AC:

AN:

14782

American (AMR)

AF:

0.0127

AC:

393

AN:

31000

Ashkenazi Jewish (ASJ)

AF:

0.0304

AC:

578

AN:

19044

East Asian (EAS)

AF:

0.000219

AC:

AN:

32034

South Asian (SAS)

AF:

0.0334

AC:

1999

AN:

59846

European-Finnish (FIN)

AF:

0.00406

AC:

135

AN:

33234

Middle Eastern (MID)

AF:

0.0676

AC:

265

AN:

3918

European-Non Finnish (NFE)

AF:

0.0185

AC:

5759

AN:

311216

Other (OTH)

AF:

0.0222

AC:

661

AN:

29826

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

499

998

1498

1997

2496

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

160

200

<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:

0.0131

AC:

1989

AN:

152258

Hom.:

Cov.:

AF XY:

0.0124

AC XY:

922

AN XY:

74462

show subpopulations

African (AFR)

AF:

0.00291

AC:

121

AN:

41550

American (AMR)

AF:

0.0131

AC:

200

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.0357

AC:

124

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.0355

AC:

171

AN:

4822

European-Finnish (FIN)

AF:

0.00358

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.0510

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0175

AC:

1191

AN:

68014

Other (OTH)

AF:

0.0190

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

100

200

300

400

500

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

140

<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:

0.0188

Hom.:

Bravo

AF:

0.0133

TwinsUK

AF:

0.0202

AC:

ALSPAC

AF:

0.0145

AC:

ExAC

AF:

0.0209

AC:

361

Asia WGS

AF:

0.0120

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

DNMBP-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_noAF

Benign

-0.41

CADD

Benign

(source)

DANN

Benign

0.90

FATHMM_MKL

Benign

0.65

LIST_S2

Benign

0.54

MetaRNN

Benign

0.0038

PhyloP100

2.1

GERP RS

4.2

Mutation Taster

=100/0

polymorphism (auto)

(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