chr9-133639992-A-G

Position:

chr9-133639992-A-G

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBA1

The NM_000787.4(DBH):c.486A>G(p.Glu162=) variant causes a splice region, synonymous change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.516 in 1,612,950 control chromosomes in the GnomAD database, including 223,425 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.53 ( 22686 hom., cov: 33)

Exomes 𝑓: 0.51 ( 200739 hom. )

Consequence

DBH
NM_000787.4 splice_region, synonymous

Scores

Splicing: ADA: 0.0003180

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 7.51

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 -18 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.38).

BP6

Variant 9-133639992-A-G is Benign according to our data. Variant chr9-133639992-A-G is described in ClinVar as [Benign]. Clinvar id is 217758.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-133639992-A-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.66 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.486A>G	p.Glu162=	splice_region_variant, synonymous_variant	2/12	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.486A>G	p.Glu162=	splice_region_variant, synonymous_variant	2/12	1	NM_000787.4	ENSP00000376776	P1
DBH	ENST00000263611.3 linkuse as main transcript	c.334-2215A>G		intron_variant		2		ENSP00000263611

Frequencies

GnomAD3 genomes

AF:

0.532

AC:

80884

AN:

151944

Hom.:

22649

Cov.:

show subpopulations

Gnomad AFR

AF:

0.666

Gnomad AMI

AF:

0.337

Gnomad AMR

AF:

0.397

Gnomad ASJ

AF:

0.454

Gnomad EAS

AF:

0.132

Gnomad SAS

AF:

0.328

Gnomad FIN

AF:

0.491

Gnomad MID

AF:

0.456

Gnomad NFE

AF:

0.541

Gnomad OTH

AF:

0.505

GnomAD3 exomes

AF:

0.449

AC:

112158

AN:

249648

Hom.:

27961

AF XY:

0.450

AC XY:

60788

AN XY:

135114

show subpopulations

Gnomad AFR exome

AF:

0.661

Gnomad AMR exome

AF:

0.285

Gnomad ASJ exome

AF:

0.461

Gnomad EAS exome

AF:

0.126

Gnomad SAS exome

AF:

0.350

Gnomad FIN exome

AF:

0.498

Gnomad NFE exome

AF:

0.538

Gnomad OTH exome

AF:

0.467

GnomAD4 exome

AF:

0.515

AC:

751787

AN:

1460888

Hom.:

200739

Cov.:

AF XY:

0.509

AC XY:

370059

AN XY:

726730

show subpopulations

Gnomad4 AFR exome

AF:

0.673

Gnomad4 AMR exome

AF:

0.299

Gnomad4 ASJ exome

AF:

0.462

Gnomad4 EAS exome

AF:

0.134

Gnomad4 SAS exome

AF:

0.354

Gnomad4 FIN exome

AF:

0.505

Gnomad4 NFE exome

AF:

0.548

Gnomad4 OTH exome

AF:

0.490

GnomAD4 genome

AF:

0.533

AC:

80984

AN:

152062

Hom.:

22686

Cov.:

AF XY:

0.521

AC XY:

38702

AN XY:

74312

show subpopulations

Gnomad4 AFR

AF:

0.666

Gnomad4 AMR

AF:

0.397

Gnomad4 ASJ

AF:

0.454

Gnomad4 EAS

AF:

0.132

Gnomad4 SAS

AF:

0.328

Gnomad4 FIN

AF:

0.491

Gnomad4 NFE

AF:

0.541

Gnomad4 OTH

AF:

0.507

Alfa

AF:

0.521

Hom.:

41202

Bravo

AF:

0.529

Asia WGS

AF:

0.275

AC:

956

AN:

3478

EpiCase

AF:

0.535

EpiControl

AF:

0.525

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Orthostatic hypotension 1

Benign:3

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. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -

not specified

Benign:2

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	This variant is associated with the following publications: (PMID: 10673769, 11904130, 25326128) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.38

CADD

Benign

DANN

Benign

0.84

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00032

dbscSNV1_RF

Benign

0.020

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