NM_000787.4:c.1734C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_000787.4(DBH):c.1734C>T(p.Asn578Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0163 in 1,613,902 control chromosomes in the GnomAD database, including 258 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.013 ( 17 hom., cov: 32)

Exomes 𝑓: 0.017 ( 241 hom. )

Consequence

DBH
NM_000787.4 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.868

Publications

6 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.73).

BP6

Variant 9-133658327-C-T is Benign according to our data. Variant chr9-133658327-C-T is described in ClinVar as Benign. ClinVar VariationId is 365673.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.868 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0126 (1924/152246) while in subpopulation NFE AF = 0.0178 (1209/67996). AF 95% confidence interval is 0.0169. There are 17 homozygotes in GnomAd4. There are 933 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 17 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DBH	NM_000787.4 link	c.1734C>T	p.Asn578Asn	synonymous_variant	Exon 12 of 12	ENST00000393056.8	NP_000778.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DBH	ENST00000393056.8 link	c.1734C>T	p.Asn578Asn	synonymous_variant	Exon 12 of 12	1	NM_000787.4	ENSP00000376776.2

Frequencies

GnomAD3 genomes

AF:

0.0126

AC:

1924

AN:

152128

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00364

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00877

Gnomad ASJ

AF:

0.0397

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0122

Gnomad FIN

AF:

0.0180

Gnomad MID

AF:

0.0348

Gnomad NFE

AF:

0.0178

Gnomad OTH

AF:

0.0144

GnomAD2 exomes

AF:

0.0157

AC:

3899

AN:

248846

AF XY:

0.0164

show subpopulations

Gnomad AFR exome

AF:

0.00252

Gnomad AMR exome

AF:

0.00487

Gnomad ASJ exome

AF:

0.0446

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0176

Gnomad NFE exome

AF:

0.0203

Gnomad OTH exome

AF:

0.0185

GnomAD4 exome

AF:

0.0167

AC:

24356

AN:

1461656

Hom.:

241

Cov.:

AF XY:

0.0169

AC XY:

12287

AN XY:

727152

show subpopulations

African (AFR)

AF:

0.00281

AC:

AN:

33478

American (AMR)

AF:

0.00555

AC:

248

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.0439

AC:

1147

AN:

26122

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39696

South Asian (SAS)

AF:

0.0171

AC:

1475

AN:

86242

European-Finnish (FIN)

AF:

0.0187

AC:

998

AN:

53394

Middle Eastern (MID)

AF:

0.0370

AC:

213

AN:

5764

European-Non Finnish (NFE)

AF:

0.0173

AC:

19203

AN:

1111862

Other (OTH)

AF:

0.0162

AC:

977

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

1228

2456

3685

4913

6141

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

700

1400

2100

2800

3500

<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:

0.0126

AC:

1924

AN:

152246

Hom.:

Cov.:

AF XY:

0.0125

AC XY:

933

AN XY:

74430

show subpopulations

African (AFR)

AF:

0.00363

AC:

151

AN:

41560

American (AMR)

AF:

0.00875

AC:

134

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.0397

AC:

138

AN:

3472

East Asian (EAS)

AF:

0.000194

AC:

AN:

5164

South Asian (SAS)

AF:

0.0125

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.0180

AC:

191

AN:

10614

Middle Eastern (MID)

AF:

0.0340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0178

AC:

1209

AN:

67996

Other (OTH)

AF:

0.0142

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

178

267

356

445

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

<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:

0.0165

Hom.:

Bravo

AF:

0.0115

Asia WGS

AF:

0.00664

AC:

AN:

3478

EpiCase

AF:

0.0168

EpiControl

AF:

0.0188

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 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 12, 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. -

DBH-related disorder

Benign:1

Jan 13, 2020

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided

Benign:1

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

BayesDel_noAF

Benign

-0.73

CADD

Benign

0.12

(source)

DANN

Benign

0.64

PhyloP100

-0.87

Mutation Taster

=100/0

polymorphism

(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