rs5320

Positions:

chr9-133642351-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000787.4(DBH):c.631G>A(p.Ala211Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0599 in 1,613,986 control chromosomes in the GnomAD database, including 3,671 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.085 ( 691 hom., cov: 32)

Exomes 𝑓: 0.057 ( 2980 hom. )

Consequence

DBH
NM_000787.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.132

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=0.0016213655).

BP6

Variant 9-133642351-G-A is Benign according to our data. Variant chr9-133642351-G-A is described in ClinVar as [Benign]. Clinvar id is 365641.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.15 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DBH	NM_000787.4 linkuse as main transcript	c.631G>A	p.Ala211Thr	missense_variant	3/12	ENST00000393056.8	NP_000778.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DBH	ENST00000393056.8 linkuse as main transcript	c.631G>A	p.Ala211Thr	missense_variant	3/12	1	NM_000787.4	ENSP00000376776	P1
DBH	ENST00000263611.3 linkuse as main transcript	c.478G>A	p.Ala160Thr	missense_variant	2/3	2		ENSP00000263611

Frequencies

GnomAD3 genomes

AF:

0.0845

AC:

12848

AN:

152018

Hom.:

684

Cov.:

show subpopulations

Gnomad AFR

AF:

0.153

Gnomad AMI

AF:

0.0384

Gnomad AMR

AF:

0.0595

Gnomad ASJ

AF:

0.0770

Gnomad EAS

AF:

0.114

Gnomad SAS

AF:

0.0798

Gnomad FIN

AF:

0.0503

Gnomad MID

AF:

0.0601

Gnomad NFE

AF:

0.0531

Gnomad OTH

AF:

0.0767

GnomAD3 exomes

AF:

0.0674

AC:

16934

AN:

251274

Hom.:

716

AF XY:

0.0679

AC XY:

9227

AN XY:

135826

show subpopulations

Gnomad AFR exome

AF:

0.152

Gnomad AMR exome

AF:

0.0391

Gnomad ASJ exome

AF:

0.0811

Gnomad EAS exome

AF:

0.112

Gnomad SAS exome

AF:

0.0811

Gnomad FIN exome

AF:

0.0535

Gnomad NFE exome

AF:

0.0547

Gnomad OTH exome

AF:

0.0623

GnomAD4 exome

AF:

0.0573

AC:

83728

AN:

1461850

Hom.:

2980

Cov.:

AF XY:

0.0580

AC XY:

42190

AN XY:

727226

show subpopulations

Gnomad4 AFR exome

AF:

0.159

Gnomad4 AMR exome

AF:

0.0427

Gnomad4 ASJ exome

AF:

0.0835

Gnomad4 EAS exome

AF:

0.121

Gnomad4 SAS exome

AF:

0.0827

Gnomad4 FIN exome

AF:

0.0544

Gnomad4 NFE exome

AF:

0.0494

Gnomad4 OTH exome

AF:

0.0668

GnomAD4 genome

AF:

0.0847

AC:

12882

AN:

152136

Hom.:

691

Cov.:

AF XY:

0.0839

AC XY:

6240

AN XY:

74378

show subpopulations

Gnomad4 AFR

AF:

0.153

Gnomad4 AMR

AF:

0.0596

Gnomad4 ASJ

AF:

0.0770

Gnomad4 EAS

AF:

0.114

Gnomad4 SAS

AF:

0.0799

Gnomad4 FIN

AF:

0.0503

Gnomad4 NFE

AF:

0.0531

Gnomad4 OTH

AF:

0.0840

Alfa

AF:

0.0634

Hom.:

910

Bravo

AF:

0.0890

TwinsUK

AF:

0.0529

AC:

196

ALSPAC

AF:

0.0493

AC:

190

ESP6500AA

AF:

0.144

AC:

635

ESP6500EA

AF:

0.0560

AC:

482

ExAC

AF:

0.0693

AC:

8415

Asia WGS

AF:

0.108

AC:

375

AN:

3478

EpiCase

AF:

0.0587

EpiControl

AF:

0.0576

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Orthostatic hypotension 1

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

DBH-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 24, 2019

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). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.060

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.60

CADD

Benign

0.034

DANN

Benign

0.70

DEOGEN2

Benign

0.15

T;.

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.020

LIST_S2

Benign

0.45

T;T

MetaRNN

Benign

0.0016

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.065

N;.

MutationTaster

Benign

1.0

PrimateAI

Benign

0.24

PROVEAN

Benign

0.97

N;.

REVEL

Benign

0.023

Sift

Benign

0.77

T;.

Sift4G

Benign

0.68

T;.

Polyphen

0.0

B;.

Vest4

0.011

MPC

0.055

ClinPred

0.0040

GERP RS

-4.7

Varity_R

0.092

gMVP

0.28

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