rs5324

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.868G>A(p.Asp290Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00406 in 1,613,278 control chromosomes in the GnomAD database, including 176 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 (★★).

Frequency

Genomes: 𝑓 0.020 ( 84 hom., cov: 32)

Exomes 𝑓: 0.0024 ( 92 hom. )

Consequence

DBH
NM_000787.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.270

Publications

18 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=0.00285092).

BP6

Variant 9-133643536-G-A is Benign according to our data. Variant chr9-133643536-G-A is described in ClinVar as Benign. ClinVar VariationId is 365650.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0646 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DBH	NM_000787.4 link	c.868G>A	p.Asp290Asn	missense_variant	Exon 4 of 12	ENST00000393056.8	NP_000778.3	P09172

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DBH	ENST00000393056.8 link	c.868G>A	p.Asp290Asn	missense_variant	Exon 4 of 12	1	NM_000787.4	ENSP00000376776.2		P09172
DBH	ENST00000263611.3 link	c.715G>A	p.Asp239Asn	missense_variant	Exon 3 of 3	2		ENSP00000263611.3		Q5T382

Frequencies

GnomAD3 genomes

AF:

0.0197

AC:

2987

AN:

151680

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0664

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00907

Gnomad ASJ

AF:

0.00548

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000417

Gnomad FIN

AF:

0.0000948

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.000633

Gnomad OTH

AF:

0.0187

GnomAD2 exomes

AF:

0.00577

AC:

1446

AN:

250800

AF XY:

0.00426

show subpopulations

Gnomad AFR exome

AF:

0.0705

Gnomad AMR exome

AF:

0.00486

Gnomad ASJ exome

AF:

0.00408

Gnomad EAS exome

AF:

0.0000545

Gnomad FIN exome

AF:

0.000324

Gnomad NFE exome

AF:

0.000547

Gnomad OTH exome

AF:

0.00326

GnomAD4 exome

AF:

0.00243

AC:

3547

AN:

1461480

Hom.:

Cov.:

AF XY:

0.00217

AC XY:

1576

AN XY:

727052

show subpopulations

African (AFR)

AF:

0.0707

AC:

2367

AN:

33480

American (AMR)

AF:

0.00523

AC:

234

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00417

AC:

109

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.000290

AC:

AN:

86248

European-Finnish (FIN)

AF:

0.000188

AC:

AN:

53082

Middle Eastern (MID)

AF:

0.00676

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.000411

AC:

457

AN:

1111960

Other (OTH)

AF:

0.00507

AC:

306

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

212

425

637

850

1062

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

160

240

320

400

<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:

0.0198

AC:

3003

AN:

151798

Hom.:

Cov.:

AF XY:

0.0192

AC XY:

1423

AN XY:

74154

show subpopulations

African (AFR)

AF:

0.0666

AC:

2758

AN:

41394

American (AMR)

AF:

0.00899

AC:

137

AN:

15236

Ashkenazi Jewish (ASJ)

AF:

0.00548

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5106

South Asian (SAS)

AF:

0.000417

AC:

AN:

4796

European-Finnish (FIN)

AF:

0.0000948

AC:

AN:

10546

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000633

AC:

AN:

67938

Other (OTH)

AF:

0.0185

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

134

267

401

534

668

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

160

<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:

0.00773

Hom.:

Bravo

AF:

0.0223

ESP6500AA

AF:

0.0681

AC:

300

ESP6500EA

AF:

0.00116

AC:

ExAC

AF:

0.00668

AC:

811

Asia WGS

AF:

0.00606

AC:

AN:

3478

EpiCase

AF:

0.00158

EpiControl

AF:

0.000771

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Orthostatic hypotension 1

Benign:2

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided

Benign:2

May 04, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.65

CADD

Benign

7.3

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.12

T;.

Eigen

Benign

-0.61

Eigen_PC

Benign

-0.67

FATHMM_MKL

Benign

0.052

LIST_S2

Benign

0.74

T;T

MetaRNN

Benign

0.0029

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.2

M;.

PhyloP100

0.27

PrimateAI

Benign

0.33

PROVEAN

Benign

-1.0

N;.

REVEL

Benign

0.063

Sift

Benign

0.23

T;.

Sift4G

Benign

0.42

T;.

Polyphen

0.24

B;.

Vest4

0.12

MVP

0.19

MPC

0.057

ClinPred

0.011

GERP RS

0.65

Varity_R

0.24

gMVP

0.50

Mutation Taster

=82/18

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over