rs4531

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000787.4(DBH):c.952G>T(p.Ala318Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0776 in 1,613,524 control chromosomes in the GnomAD database, including 5,350 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.078 ( 536 hom., cov: 34)

Exomes 𝑓: 0.078 ( 4814 hom. )

Consequence

DBH
NM_000787.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.970

Publications

33 publications found

Variant links:

Genes affected

DBH (HGNC:2689): (dopamine beta-hydroxylase) The protein encoded by this gene is an oxidoreductase belonging to the copper type II, ascorbate-dependent monooxygenase family. The encoded protein, expressed in neuroscretory vesicles and chromaffin granules of the adrenal medulla, catalyzes the conversion of dopamine to norepinephrine, which functions as both a hormone and as the main neurotransmitter of the sympathetic nervous system. The enzyme encoded by this gene exists exists in both soluble and membrane-bound forms, depending on the absence or presence, respectively, of a signal peptide. Mutations in this gene cause dopamine beta-hydroxylate deficiency in human patients, characterized by deficits in autonomic and cardiovascular function, including hypotension and ptosis. Polymorphisms in this gene may play a role in a variety of psychiatric disorders. [provided by RefSeq, Aug 2017]

DBH Gene-Disease associations (from GenCC):

orthostatic hypotension 1
Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)

DBH 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=0.0028128922).

BP6

Variant 9-133644248-G-T is Benign according to our data. Variant chr9-133644248-G-T is described in ClinVar as Benign. ClinVar VariationId is 365652.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.112 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000787.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DBH	NM_000787.4	MANE Select	c.952G>T	p.Ala318Ser	missense	Exon 5 of 12	NP_000778.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DBH	ENST00000393056.8	TSL:1 MANE Select	c.952G>T	p.Ala318Ser	missense	Exon 5 of 12	ENSP00000376776.2	P09172
	DBH	ENST00000860939.1		c.952G>T	p.Ala318Ser	missense	Exon 5 of 12	ENSP00000530998.1

Frequencies

GnomAD3 genomes

AF:

0.0782

AC:

11898

AN:

152152

Hom.:

535

Cov.:

show subpopulations

Gnomad AFR

AF:

0.115

Gnomad AMI

AF:

0.0362

Gnomad AMR

AF:

0.0405

Gnomad ASJ

AF:

0.0530

Gnomad EAS

AF:

0.00519

Gnomad SAS

AF:

0.0465

Gnomad FIN

AF:

0.0438

Gnomad MID

AF:

0.0570

Gnomad NFE

AF:

0.0797

Gnomad OTH

AF:

0.0683

GnomAD2 exomes

AF:

0.0632

AC:

15879

AN:

251432

AF XY:

0.0627

show subpopulations

Gnomad AFR exome

AF:

0.120

Gnomad AMR exome

AF:

0.0338

Gnomad ASJ exome

AF:

0.0540

Gnomad EAS exome

AF:

0.00326

Gnomad FIN exome

AF:

0.0468

Gnomad NFE exome

AF:

0.0809

Gnomad OTH exome

AF:

0.0668

GnomAD4 exome

AF:

0.0775

AC:

113267

AN:

1461254

Hom.:

4814

Cov.:

AF XY:

0.0759

AC XY:

55167

AN XY:

726952

show subpopulations

African (AFR)

AF:

0.122

AC:

4073

AN:

33468

American (AMR)

AF:

0.0352

AC:

1573

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0532

AC:

1391

AN:

26132

East Asian (EAS)

AF:

0.00708

AC:

281

AN:

39700

South Asian (SAS)

AF:

0.0490

AC:

4224

AN:

86250

European-Finnish (FIN)

AF:

0.0495

AC:

2641

AN:

53398

Middle Eastern (MID)

AF:

0.0444

AC:

256

AN:

5766

European-Non Finnish (NFE)

AF:

0.0849

AC:

94347

AN:

1111438

Other (OTH)

AF:

0.0742

AC:

4481

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

5835

11671

17506

23342

29177

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3494

6988

10482

13976

17470

<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:

0.0782

AC:

11914

AN:

152270

Hom.:

536

Cov.:

AF XY:

0.0744

AC XY:

5537

AN XY:

74456

show subpopulations

African (AFR)

AF:

0.115

AC:

4779

AN:

41544

American (AMR)

AF:

0.0405

AC:

619

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0530

AC:

184

AN:

3472

East Asian (EAS)

AF:

0.00520

AC:

AN:

5190

South Asian (SAS)

AF:

0.0469

AC:

226

AN:

4816

European-Finnish (FIN)

AF:

0.0438

AC:

465

AN:

10616

Middle Eastern (MID)

AF:

0.0544

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0797

AC:

5420

AN:

68008

Other (OTH)

AF:

0.0685

AC:

145

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

560

1119

1679

2238

2798

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

130

260

390

520

650

<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:

0.0759

Hom.:

1311

Bravo

AF:

0.0809

TwinsUK

AF:

0.0790

AC:

293

ALSPAC

AF:

0.0893

AC:

344

ESP6500AA

AF:

0.120

AC:

530

ESP6500EA

AF:

0.0777

AC:

668

ExAC

AF:

0.0665

AC:

8069

Asia WGS

AF:

0.0470

AC:

164

AN:

3478

EpiCase

AF:

0.0765

EpiControl

AF:

0.0736

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Orthostatic hypotension 1 (2)

DBH-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.71

BayesDel_noAF

Benign

-0.70

CADD

Benign

2.7

(source)

DANN

Benign

0.85

DEOGEN2

Benign

0.10

Eigen

Benign

-0.99

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.60

LIST_S2

Benign

0.81

MetaRNN

Benign

0.0028

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.5

PhyloP100

0.97

PrimateAI

Benign

0.43

PROVEAN

Benign

-0.76

REVEL

Benign

0.062

Sift

Benign

0.24

Sift4G

Benign

0.26

Polyphen

0.067

Vest4

0.33

MPC

0.29

ClinPred

0.012

GERP RS

-0.85

Varity_R

0.17

gMVP

0.74

Mutation Taster

=92/8

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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