9-133658547-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.*100C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.202 in 1,336,366 control chromosomes in the GnomAD database, including 28,781 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.20 ( 3316 hom., cov: 32)

Exomes 𝑓: 0.20 ( 25465 hom. )

Consequence

DBH
NM_000787.4 3_prime_UTR

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.0780

Publications

27 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 (BayesDel_noAF=-0.77).

BP6

Variant 9-133658547-C-T is Benign according to our data. Variant chr9-133658547-C-T is described in ClinVar as Benign. ClinVar VariationId is 365678.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.364 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DBH	NM_000787.4 link	c.*100C>T		3_prime_UTR_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.*100C>T		3_prime_UTR_variant	Exon 12 of 12	1	NM_000787.4	ENSP00000376776.2

Frequencies

GnomAD3 genomes

AF:

0.203

AC:

30844

AN:

152080

Hom.:

3319

Cov.:

show subpopulations

Gnomad AFR

AF:

0.199

Gnomad AMI

AF:

0.0868

Gnomad AMR

AF:

0.226

Gnomad ASJ

AF:

0.189

Gnomad EAS

AF:

0.377

Gnomad SAS

AF:

0.310

Gnomad FIN

AF:

0.149

Gnomad MID

AF:

0.215

Gnomad NFE

AF:

0.189

Gnomad OTH

AF:

0.201

GnomAD4 exome

AF:

0.202

AC:

238629

AN:

1184168

Hom.:

25465

Cov.:

AF XY:

0.204

AC XY:

117499

AN XY:

576088

show subpopulations

African (AFR)

AF:

0.193

AC:

5037

AN:

26164

American (AMR)

AF:

0.262

AC:

5247

AN:

20050

Ashkenazi Jewish (ASJ)

AF:

0.196

AC:

3571

AN:

18190

East Asian (EAS)

AF:

0.390

AC:

12795

AN:

32798

South Asian (SAS)

AF:

0.299

AC:

17036

AN:

56980

European-Finnish (FIN)

AF:

0.156

AC:

6569

AN:

42158

Middle Eastern (MID)

AF:

0.218

AC:

753

AN:

3458

European-Non Finnish (NFE)

AF:

0.190

AC:

177144

AN:

934618

Other (OTH)

AF:

0.211

AC:

10477

AN:

49752

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

8882

17765

26647

35530

44412

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

6540

13080

19620

26160

32700

<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:

0.203

AC:

30860

AN:

152198

Hom.:

3316

Cov.:

AF XY:

0.205

AC XY:

15277

AN XY:

74434

show subpopulations

African (AFR)

AF:

0.199

AC:

8275

AN:

41534

American (AMR)

AF:

0.226

AC:

3463

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.189

AC:

657

AN:

3472

East Asian (EAS)

AF:

0.378

AC:

1948

AN:

5158

South Asian (SAS)

AF:

0.309

AC:

1490

AN:

4818

European-Finnish (FIN)

AF:

0.149

AC:

1586

AN:

10618

Middle Eastern (MID)

AF:

0.201

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.189

AC:

12883

AN:

67986

Other (OTH)

AF:

0.199

AC:

420

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1279

2558

3836

5115

6394

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

356

712

1068

1424

1780

<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:

0.192

Hom.:

4084

Bravo

AF:

0.207

Asia WGS

AF:

0.321

AC:

1118

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Orthostatic hypotension 1

Benign:2

Mar 06, 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. -

Jan 15, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

May 11, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 25975715, 20498626) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.77

CADD

Benign

6.2

(source)

DANN

Benign

0.78

PhyloP100

-0.078

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over