NM_000787.4:c.631G>A

Variant names:

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.631G>A(p.Ala211Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0599 in 1,613,986 control chromosomes in the GnomAD database, including 3,671 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A211V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.085 ( 691 hom., cov: 32)

Exomes 𝑓: 0.057 ( 2980 hom. )

Consequence

DBH
NM_000787.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.132

Publications

39 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet

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=0.0016213655).

BP6

Variant 9-133642351-G-A is Benign according to our data. Variant chr9-133642351-G-A is described in ClinVar as Benign. ClinVar VariationId is 365641.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.15 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.631G>A	p.Ala211Thr	missense	Exon 3 of 12	NP_000778.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
DBH	ENST00000393056.8	TSL:1 MANE Select	c.631G>A	p.Ala211Thr	missense	Exon 3 of 12	ENSP00000376776.2
DBH	ENST00000860939.1		c.631G>A	p.Ala211Thr	missense	Exon 3 of 12	ENSP00000530998.1
DBH	ENST00000263611.3	TSL:2	c.478G>A	p.Ala160Thr	missense	Exon 2 of 3	ENSP00000263611.3

Frequencies

GnomAD3 genomes

AF:

0.0845

AC:

12848

AN:

152018

Hom.:

684

Cov.:

show subpopulations

Gnomad AFR

AF:

0.153

Gnomad AMI

AF:

0.0384

Gnomad AMR

AF:

0.0595

Gnomad ASJ

AF:

0.0770

Gnomad EAS

AF:

0.114

Gnomad SAS

AF:

0.0798

Gnomad FIN

AF:

0.0503

Gnomad MID

AF:

0.0601

Gnomad NFE

AF:

0.0531

Gnomad OTH

AF:

0.0767

GnomAD2 exomes

AF:

0.0674

AC:

16934

AN:

251274

AF XY:

0.0679

show subpopulations

Gnomad AFR exome

AF:

0.152

Gnomad AMR exome

AF:

0.0391

Gnomad ASJ exome

AF:

0.0811

Gnomad EAS exome

AF:

0.112

Gnomad FIN exome

AF:

0.0535

Gnomad NFE exome

AF:

0.0547

Gnomad OTH exome

AF:

0.0623

GnomAD4 exome

AF:

0.0573

AC:

83728

AN:

1461850

Hom.:

2980

Cov.:

AF XY:

0.0580

AC XY:

42190

AN XY:

727226

show subpopulations

African (AFR)

AF:

0.159

AC:

5323

AN:

33478

American (AMR)

AF:

0.0427

AC:

1909

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.0835

AC:

2182

AN:

26136

East Asian (EAS)

AF:

0.121

AC:

4807

AN:

39696

South Asian (SAS)

AF:

0.0827

AC:

7136

AN:

86258

European-Finnish (FIN)

AF:

0.0544

AC:

2908

AN:

53410

Middle Eastern (MID)

AF:

0.0860

AC:

496

AN:

5768

European-Non Finnish (NFE)

AF:

0.0494

AC:

54934

AN:

1111990

Other (OTH)

AF:

0.0668

AC:

4033

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

5516

11032

16547

22063

27579

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2136

4272

6408

8544

10680

<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:

0.0847

AC:

12882

AN:

152136

Hom.:

691

Cov.:

AF XY:

0.0839

AC XY:

6240

AN XY:

74378

show subpopulations

African (AFR)

AF:

0.153

AC:

6359

AN:

41484

American (AMR)

AF:

0.0596

AC:

911

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.0770

AC:

267

AN:

3466

East Asian (EAS)

AF:

0.114

AC:

587

AN:

5166

South Asian (SAS)

AF:

0.0799

AC:

385

AN:

4820

European-Finnish (FIN)

AF:

0.0503

AC:

533

AN:

10604

Middle Eastern (MID)

AF:

0.0612

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0531

AC:

3610

AN:

67988

Other (OTH)

AF:

0.0840

AC:

177

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

596

1191

1787

2382

2978

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

146

292

438

584

730

<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:

0.0671

Hom.:

1480

Bravo

AF:

0.0890

TwinsUK

AF:

0.0529

AC:

196

ALSPAC

AF:

0.0493

AC:

190

ESP6500AA

AF:

0.144

AC:

635

ESP6500EA

AF:

0.0560

AC:

482

ExAC

AF:

0.0693

AC:

8415

Asia WGS

AF:

0.108

AC:

375

AN:

3478

EpiCase

AF:

0.0587

EpiControl

AF:

0.0576

ClinVar

ClinVar submissions as Germline

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

0.060

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.60

CADD

Benign

0.034

(source)

DANN

Benign

0.70

DEOGEN2

Benign

0.15

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.020

LIST_S2

Benign

0.45

MetaRNN

Benign

0.0016

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.065

PhyloP100

-0.13

PrimateAI

Benign

0.24

PROVEAN

Benign

0.97

REVEL

Benign

0.023

Sift

Benign

0.77

Sift4G

Benign

0.68

Polyphen

0.0

Vest4

0.011

MPC

0.055

ClinPred

0.0040

GERP RS

-4.7

Varity_R

0.092

gMVP

0.28

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