9-133639992-A-G

Variant names:

• chr9-133639992-A-G
• rs1108580
• NM_000787.4:c.486A>G

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_000787.4(DBH):​c.486A>G​(p.Glu162Glu) 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
• Publications: 81 publications found

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 Gene-Disease associations (from GenCC):

• orthostatic hypotension 1

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 217758.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.66 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DBH	NM_000787.4	c.486A>G	p.Glu162Glu	splice_region_variant, synonymous_variant	Exon 2 of 12	ENST00000393056.8	NP_000778.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DBH	ENST00000393056.8	c.486A>G	p.Glu162Glu	splice_region_variant, synonymous_variant	Exon 2 of 12	1	NM_000787.4	ENSP00000376776.2
DBH	ENST00000263611.3	c.334-2215A>G		intron_variant	Intron 1 of 2	2		ENSP00000263611.3

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

GnomAD2 exomes AF: 0.449 AC: 112158 AN: 249648 AF XY: 0.450

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 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

African (AFR) AF: 0.673 AC: 22517 AN: 33474

American (AMR) AF: 0.299 AC: 13340 AN: 44648

Ashkenazi Jewish (ASJ) AF: 0.462 AC: 12077 AN: 26124

East Asian (EAS) AF: 0.134 AC: 5302 AN: 39692

South Asian (SAS) AF: 0.354 AC: 30544 AN: 86190

European-Finnish (FIN) AF: 0.505 AC: 26798 AN: 53054

Middle Eastern (MID) AF: 0.436 AC: 2510 AN: 5760

European-Non Finnish (NFE) AF: 0.548 AC: 609154 AN: 1111590

Other (OTH) AF: 0.490 AC: 29545 AN: 60356

GnomAD4 genome AF: 0.533 AC: 80984 AN: 152062 Hom.: 22686 Cov.: 33 AF XY: 0.521 AC XY: 38702 AN XY: 74312

African (AFR) AF: 0.666 AC: 27649 AN: 41500

American (AMR) AF: 0.397 AC: 6060 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.454 AC: 1574 AN: 3470

East Asian (EAS) AF: 0.132 AC: 679 AN: 5156

South Asian (SAS) AF: 0.328 AC: 1584 AN: 4822

European-Finnish (FIN) AF: 0.491 AC: 5183 AN: 10554

Middle Eastern (MID) AF: 0.476 AC: 140 AN: 294

European-Non Finnish (NFE) AF: 0.541 AC: 36737 AN: 67960

Other (OTH) AF: 0.507 AC: 1072 AN: 2116

Alfa AF: 0.529 Hom.: 82497

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

Submissions by phenotype

Orthostatic hypotension 1 Benign:3

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 specified Benign:2

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

May 04, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		7.5
Mutation Taster		=7/93	polymorphism (auto)

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

Other links and lift over

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