9-133636447-G-A

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000787.4(DBH):c.76G>A(p.Val26Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0042 in 1,612,912 control chromosomes in the GnomAD database, including 41 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0038 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0042 ( 38 hom. )

Consequence

DBH
NM_000787.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.20

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008224636).

BP6

Variant 9-133636447-G-A is Benign according to our data. Variant chr9-133636447-G-A is described in ClinVar as [Benign]. Clinvar id is 779694.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00377 (575/152328) while in subpopulation SAS AF= 0.0135 (65/4830). AF 95% confidence interval is 0.0108. There are 3 homozygotes in gnomad4. There are 298 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DBH	NM_000787.4 link	c.76G>A	p.Val26Met	missense_variant	Exon 1 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.76G>A	p.Val26Met	missense_variant	Exon 1 of 12	1	NM_000787.4	ENSP00000376776.2		P09172
DBH	ENST00000263611.3 link	c.70G>A	p.Val24Met	missense_variant	Exon 1 of 3	2		ENSP00000263611.3		Q5T382

Frequencies

GnomAD3 genomes

AF:

0.00378

AC:

575

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000651

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00111

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0134

Gnomad FIN

AF:

0.00772

Gnomad MID

AF:

0.00637

Gnomad NFE

AF:

0.00554

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.00512

AC:

1283

AN:

250370

Hom.:

AF XY:

0.00583

AC XY:

791

AN XY:

135590

show subpopulations

Gnomad AFR exome

AF:

0.000742

Gnomad AMR exome

AF:

0.00133

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0125

Gnomad FIN exome

AF:

0.00789

Gnomad NFE exome

AF:

0.00569

Gnomad OTH exome

AF:

0.00490

GnomAD4 exome

AF:

0.00425

AC:

6205

AN:

1460584

Hom.:

Cov.:

AF XY:

0.00466

AC XY:

3383

AN XY:

726564

show subpopulations

Gnomad4 AFR exome

AF:

0.000687

Gnomad4 AMR exome

AF:

0.00130

Gnomad4 ASJ exome

AF:

0.000191

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0121

Gnomad4 FIN exome

AF:

0.00809

Gnomad4 NFE exome

AF:

0.00392

Gnomad4 OTH exome

AF:

0.00402

GnomAD4 genome

AF:

0.00377

AC:

575

AN:

152328

Hom.:

Cov.:

AF XY:

0.00400

AC XY:

298

AN XY:

74498

show subpopulations

Gnomad4 AFR

AF:

0.000649

Gnomad4 AMR

AF:

0.00111

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0135

Gnomad4 FIN

AF:

0.00772

Gnomad4 NFE

AF:

0.00554

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.00485

Hom.:

Bravo

AF:

0.00249

TwinsUK

AF:

0.00297

AC:

ALSPAC

AF:

0.00337

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00453

AC:

ExAC

AF:

0.00577

AC:

700

Asia WGS

AF:

0.00606

AC:

AN:

3478

EpiCase

AF:

0.00513

EpiControl

AF:

0.00522

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

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Aug 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DBH: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.36

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.26

T;.

Eigen

Uncertain

0.34

Eigen_PC

Uncertain

0.33

FATHMM_MKL

Benign

0.73

LIST_S2

Uncertain

0.90

D;D

MetaRNN

Benign

0.0082

T;T

MetaSVM

Benign

-0.81

MutationAssessor

Uncertain

2.7

M;.

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-0.67

N;.

REVEL

Benign

0.14

Sift

Benign

0.047

D;.

Sift4G

Benign

0.12

T;.

Polyphen

0.93

P;.

Vest4

0.43

MVP

0.59

MPC

0.25

ClinPred

0.025

GERP RS

4.6

Varity_R

0.053

gMVP

0.50

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over