rs6271

Variant summary

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

The NM_000787.4(DBH):c.1645C>T(p.Arg549Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0615 in 1,614,048 control chromosomes in the GnomAD database, including 3,557 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R549H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.047 ( 239 hom., cov: 32)

Exomes 𝑓: 0.063 ( 3318 hom. )

Consequence

DBH
NM_000787.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 3.43

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:

DBH-AS1 (HGNC:24155): (DBH antisense RNA 1)

DBH-AS1 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=0.0033020675).

BP6

Variant 9-133657152-C-T is Benign according to our data. Variant chr9-133657152-C-T is described in ClinVar as [Benign]. Clinvar id is 365671.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0684 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DBH	NM_000787.4 linkuse as main transcript	c.1645C>T	p.Arg549Cys	missense_variant	11/12	ENST00000393056.8
DBH-AS1	NR_102735.1 linkuse as main transcript	n.257G>A		non_coding_transcript_exon_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DBH	ENST00000393056.8 linkuse as main transcript	c.1645C>T	p.Arg549Cys	missense_variant	11/12	1	NM_000787.4	P1
DBH-AS1	ENST00000425189.1 linkuse as main transcript	n.162G>A		non_coding_transcript_exon_variant	1/2	1

Frequencies

GnomAD3 genomes

AF:

0.0475

AC:

7231

AN:

152160

Hom.:

239

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0138

Gnomad AMI

AF:

0.0406

Gnomad AMR

AF:

0.0492

Gnomad ASJ

AF:

0.0622

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00787

Gnomad FIN

AF:

0.0666

Gnomad MID

AF:

0.0570

Gnomad NFE

AF:

0.0700

Gnomad OTH

AF:

0.0592

GnomAD3 exomes

AF:

0.0461

AC:

11580

AN:

251400

Hom.:

357

AF XY:

0.0460

AC XY:

6258

AN XY:

135896

show subpopulations

Gnomad AFR exome

AF:

0.0113

Gnomad AMR exome

AF:

0.0346

Gnomad ASJ exome

AF:

0.0602

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00885

Gnomad FIN exome

AF:

0.0642

Gnomad NFE exome

AF:

0.0669

Gnomad OTH exome

AF:

0.0533

GnomAD4 exome

AF:

0.0629

AC:

92009

AN:

1461770

Hom.:

3318

Cov.:

AF XY:

0.0615

AC XY:

44710

AN XY:

727184

show subpopulations

Gnomad4 AFR exome

AF:

0.0103

Gnomad4 AMR exome

AF:

0.0367

Gnomad4 ASJ exome

AF:

0.0606

Gnomad4 EAS exome

AF:

0.000151

Gnomad4 SAS exome

AF:

0.00947

Gnomad4 FIN exome

AF:

0.0648

Gnomad4 NFE exome

AF:

0.0723

Gnomad4 OTH exome

AF:

0.0588

GnomAD4 genome

AF:

0.0475

AC:

7229

AN:

152278

Hom.:

239

Cov.:

AF XY:

0.0466

AC XY:

3467

AN XY:

74456

show subpopulations

Gnomad4 AFR

AF:

0.0138

Gnomad4 AMR

AF:

0.0491

Gnomad4 ASJ

AF:

0.0622

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.00787

Gnomad4 FIN

AF:

0.0666

Gnomad4 NFE

AF:

0.0700

Gnomad4 OTH

AF:

0.0586

Alfa

AF:

0.0614

Hom.:

213

Bravo

AF:

0.0458

TwinsUK

AF:

0.0763

AC:

283

ALSPAC

AF:

0.0771

AC:

297

ESP6500AA

AF:

0.0129

AC:

ESP6500EA

AF:

0.0763

AC:

656

ExAC

AF:

0.0453

AC:

5502

Asia WGS

AF:

0.00635

AC:

AN:

3478

EpiCase

AF:

0.0716

EpiControl

AF:

0.0698

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Orthostatic hypotension 1

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 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. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 22, 2019

This variant is associated with the following publications: (PMID: 21085059, 30817802, 16152569, 22028891, 21509519) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.50

Cadd

Benign

Dann

Uncertain

1.0

DEOGEN2

Benign

0.42

Eigen

Benign

-0.084

Eigen_PC

Benign

-0.20

FATHMM_MKL

Benign

0.64

LIST_S2

Uncertain

0.91

MetaRNN

Benign

0.0033

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.7

MutationTaster

Benign

1.0

PrimateAI

Benign

0.40

PROVEAN

Benign

-1.7

REVEL

Benign

0.18

Sift

Benign

0.10

Sift4G

Uncertain

0.054

Polyphen

0.98

Vest4

0.22

MPC

0.32

ClinPred

0.032

GERP RS

4.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.11

gMVP

0.85

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