9-133644248-G-T

Position:

chr9-133644248-G-T

Variant summary

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

The NM_000787.4(DBH):c.952G>T(p.Ala318Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0776 in 1,613,524 control chromosomes in the GnomAD database, including 5,350 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 0.078 ( 536 hom., cov: 34)

Exomes 𝑓: 0.078 ( 4814 hom. )

Consequence

DBH
NM_000787.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.970

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=0.0028128922).

BP6

Variant 9-133644248-G-T is Benign according to our data. Variant chr9-133644248-G-T is described in ClinVar as [Benign]. Clinvar id is 365652.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-133644248-G-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.112 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.952G>T	p.Ala318Ser	missense_variant	5/12	ENST00000393056.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DBH	ENST00000393056.8 linkuse as main transcript	c.952G>T	p.Ala318Ser	missense_variant	5/12	1	NM_000787.4	P1

Frequencies

GnomAD3 genomes

AF:

0.0782

AC:

11898

AN:

152152

Hom.:

535

Cov.:

show subpopulations

Gnomad AFR

AF:

0.115

Gnomad AMI

AF:

0.0362

Gnomad AMR

AF:

0.0405

Gnomad ASJ

AF:

0.0530

Gnomad EAS

AF:

0.00519

Gnomad SAS

AF:

0.0465

Gnomad FIN

AF:

0.0438

Gnomad MID

AF:

0.0570

Gnomad NFE

AF:

0.0797

Gnomad OTH

AF:

0.0683

GnomAD3 exomes

AF:

0.0632

AC:

15879

AN:

251432

Hom.:

659

AF XY:

0.0627

AC XY:

8525

AN XY:

135894

show subpopulations

Gnomad AFR exome

AF:

0.120

Gnomad AMR exome

AF:

0.0338

Gnomad ASJ exome

AF:

0.0540

Gnomad EAS exome

AF:

0.00326

Gnomad SAS exome

AF:

0.0503

Gnomad FIN exome

AF:

0.0468

Gnomad NFE exome

AF:

0.0809

Gnomad OTH exome

AF:

0.0668

GnomAD4 exome

AF:

0.0775

AC:

113267

AN:

1461254

Hom.:

4814

Cov.:

AF XY:

0.0759

AC XY:

55167

AN XY:

726952

show subpopulations

Gnomad4 AFR exome

AF:

0.122

Gnomad4 AMR exome

AF:

0.0352

Gnomad4 ASJ exome

AF:

0.0532

Gnomad4 EAS exome

AF:

0.00708

Gnomad4 SAS exome

AF:

0.0490

Gnomad4 FIN exome

AF:

0.0495

Gnomad4 NFE exome

AF:

0.0849

Gnomad4 OTH exome

AF:

0.0742

GnomAD4 genome

AF:

0.0782

AC:

11914

AN:

152270

Hom.:

536

Cov.:

AF XY:

0.0744

AC XY:

5537

AN XY:

74456

show subpopulations

Gnomad4 AFR

AF:

0.115

Gnomad4 AMR

AF:

0.0405

Gnomad4 ASJ

AF:

0.0530

Gnomad4 EAS

AF:

0.00520

Gnomad4 SAS

AF:

0.0469

Gnomad4 FIN

AF:

0.0438

Gnomad4 NFE

AF:

0.0797

Gnomad4 OTH

AF:

0.0685

Alfa

AF:

0.0730

Hom.:

810

Bravo

AF:

0.0809

TwinsUK

AF:

0.0790

AC:

293

ALSPAC

AF:

0.0893

AC:

344

ESP6500AA

AF:

0.120

AC:

530

ESP6500EA

AF:

0.0777

AC:

668

ExAC

AF:

0.0665

AC:

8069

Asia WGS

AF:

0.0470

AC:

164

AN:

3478

EpiCase

AF:

0.0765

EpiControl

AF:

0.0736

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 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	- -

DBH-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 20, 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

0.083

BayesDel_addAF

Benign

-0.71

BayesDel_noAF

Benign

-0.70

CADD

Benign

2.7

DANN

Benign

0.85

DEOGEN2

Benign

0.10

Eigen

Benign

-0.99

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.60

LIST_S2

Benign

0.81

MetaRNN

Benign

0.0028

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.5

MutationTaster

Benign

1.0

PrimateAI

Benign

0.43

PROVEAN

Benign

-0.76

REVEL

Benign

0.062

Sift

Benign

0.24

Sift4G

Benign

0.26

Polyphen

0.067

Vest4

0.33

MPC

0.29

ClinPred

0.012

GERP RS

-0.85

Varity_R

0.17

gMVP

0.74

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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