9-133657152-C-T

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.1645C>T(p.Arg549Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0615 in 1,614,048 control chromosomes in the GnomAD database, including 3,557 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 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. R549S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.047 ( 239 hom., cov: 32)

Exomes 𝑓: 0.063 ( 3318 hom. )

Consequence

DBH
NM_000787.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 3.43

Publications

82 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 links:

DBH-AS1 (HGNC:24155): (DBH antisense RNA 1)

DBH-AS1 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=0.0033020675).

BP6

Variant 9-133657152-C-T is Benign according to our data. Variant chr9-133657152-C-T is described in ClinVar as Benign. ClinVar VariationId is 365671.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0684 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.1645C>T	p.Arg549Cys	missense	Exon 11 of 12	NP_000778.3
	DBH-AS1	NR_102735.1		n.257G>A		non_coding_transcript_exon	Exon 1 of 2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DBH	ENST00000393056.8	TSL:1 MANE Select	c.1645C>T	p.Arg549Cys	missense	Exon 11 of 12	ENSP00000376776.2	P09172
DBH-AS1	ENST00000425189.1	TSL:1	n.162G>A		non_coding_transcript_exon	Exon 1 of 2
DBH	ENST00000860939.1		c.1645C>T	p.Arg549Cys	missense	Exon 11 of 12	ENSP00000530998.1

Frequencies

GnomAD3 genomes

AF:

0.0475

AC:

7231

AN:

152160

Hom.:

239

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0138

Gnomad AMI

AF:

0.0406

Gnomad AMR

AF:

0.0492

Gnomad ASJ

AF:

0.0622

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00787

Gnomad FIN

AF:

0.0666

Gnomad MID

AF:

0.0570

Gnomad NFE

AF:

0.0700

Gnomad OTH

AF:

0.0592

GnomAD2 exomes

AF:

0.0461

AC:

11580

AN:

251400

AF XY:

0.0460

show subpopulations

Gnomad AFR exome

AF:

0.0113

Gnomad AMR exome

AF:

0.0346

Gnomad ASJ exome

AF:

0.0602

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.0642

Gnomad NFE exome

AF:

0.0669

Gnomad OTH exome

AF:

0.0533

GnomAD4 exome

AF:

0.0629

AC:

92009

AN:

1461770

Hom.:

3318

Cov.:

AF XY:

0.0615

AC XY:

44710

AN XY:

727184

show subpopulations

African (AFR)

AF:

0.0103

AC:

344

AN:

33480

American (AMR)

AF:

0.0367

AC:

1641

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.0606

AC:

1583

AN:

26134

East Asian (EAS)

AF:

0.000151

AC:

AN:

39700

South Asian (SAS)

AF:

0.00947

AC:

817

AN:

86258

European-Finnish (FIN)

AF:

0.0648

AC:

3458

AN:

53324

Middle Eastern (MID)

AF:

0.0392

AC:

226

AN:

5768

European-Non Finnish (NFE)

AF:

0.0723

AC:

80381

AN:

1111996

Other (OTH)

AF:

0.0588

AC:

3553

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

5188

10376

15565

20753

25941

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2894

5788

8682

11576

14470

<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:

0.0475

AC:

7229

AN:

152278

Hom.:

239

Cov.:

AF XY:

0.0466

AC XY:

3467

AN XY:

74456

show subpopulations

African (AFR)

AF:

0.0138

AC:

573

AN:

41562

American (AMR)

AF:

0.0491

AC:

752

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.0622

AC:

216

AN:

3470

East Asian (EAS)

AF:

0.000386

AC:

AN:

5182

South Asian (SAS)

AF:

0.00787

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0666

AC:

706

AN:

10596

Middle Eastern (MID)

AF:

0.0578

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0700

AC:

4764

AN:

68016

Other (OTH)

AF:

0.0586

AC:

124

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

357

715

1072

1430

1787

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

168

252

336

420

<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:

0.0595

Hom.:

260

Bravo

AF:

0.0458

TwinsUK

AF:

0.0763

AC:

283

ALSPAC

AF:

0.0771

AC:

297

ESP6500AA

AF:

0.0129

AC:

ESP6500EA

AF:

0.0763

AC:

656

ExAC

AF:

0.0453

AC:

5502

Asia WGS

AF:

0.00635

AC:

AN:

3478

EpiCase

AF:

0.0716

EpiControl

AF:

0.0698

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)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.50

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.42

Eigen

Benign

-0.084

Eigen_PC

Benign

-0.20

FATHMM_MKL

Benign

0.64

LIST_S2

Uncertain

0.91

MetaRNN

Benign

0.0033

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.7

PhyloP100

3.4

PrimateAI

Benign

0.40

PROVEAN

Benign

-1.7

REVEL

Benign

0.18

Sift

Benign

0.10

Sift4G

Uncertain

0.054

Polyphen

0.98

Vest4

0.22

MPC

0.32

ClinPred

0.032

GERP RS

4.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.11

gMVP

0.85

Mutation Taster

=91/9

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