rs1108580

chr9-133639992-A-G

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

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. 2/2 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:6
• Conservation: PhyloP100: 7.51

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]

ACMG classification

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	UniProt
DBH	NM_000787.4	c.486A>G	p.Glu162=	splice_region_variant, synonymous_variant	2/12	ENST00000393056.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DBH	ENST00000393056.8	c.486A>G	p.Glu162=	splice_region_variant, synonymous_variant	2/12	1	NM_000787.4	P1
DBH	ENST00000263611.3	c.334-2215A>G		intron_variant		2

Frequencies

GnomAD3 genomes AF: 0.532 AC: 80884 AN: 151944 Hom.: 22649 Cov.: 33

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

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.: 55 AF XY: 0.509 AC XY: 370059 AN XY: 726730

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.: 33 AF XY: 0.521 AC XY: 38702 AN XY: 74312

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:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Orthostatic hypotension 1 Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -
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	Invitae	Jan 31, 2024	- -

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:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 04, 2021

This variant is associated with the following publications: (PMID: 10673769, 11904130, 25326128) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
Cadd	Benign	13
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

Other links and lift over

dbSNP: rs1108580; hg19: chr9-136505114; COSMIC: COSV55040789;