9-133637199-G-A

Variant names:

• chr9-133637199-G-A
• rs3025382
• NM_000787.4:c.339+489G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000787.4(DBH):​c.339+489G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.152 in 152,242 control chromosomes in the GnomAD database, including 2,218 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.15 (2218 hom., cov: 33)
• Consequence: DBH NM_000787.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.84
• Publications: 9 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.263 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000787.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DBH	NM_000787.4	MANE Select	c.339+489G>A		intron	N/A	NP_000778.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DBH	ENST00000393056.8	TSL:1 MANE Select	c.339+489G>A		intron	N/A	ENSP00000376776.2
	DBH	ENST00000263611.3	TSL:2	c.333+489G>A		intron	N/A	ENSP00000263611.3

Frequencies

GnomAD3 genomes AF: 0.152 AC: 23132 AN: 152124 Hom.: 2215 Cov.: 33

Gnomad AFR AF: 0.267

Gnomad AMI AF: 0.0395

Gnomad AMR AF: 0.0882

Gnomad ASJ AF: 0.110

Gnomad EAS AF: 0.0249

Gnomad SAS AF: 0.0728

Gnomad FIN AF: 0.106

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.123

Gnomad OTH AF: 0.136

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.152 AC: 23158 AN: 152242 Hom.: 2218 Cov.: 33 AF XY: 0.147 AC XY: 10939 AN XY: 74424

African (AFR) AF: 0.267 AC: 11094 AN: 41520

American (AMR) AF: 0.0881 AC: 1349 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.110 AC: 382 AN: 3470

East Asian (EAS) AF: 0.0252 AC: 130 AN: 5164

South Asian (SAS) AF: 0.0733 AC: 354 AN: 4828

European-Finnish (FIN) AF: 0.106 AC: 1127 AN: 10610

Middle Eastern (MID) AF: 0.0646 AC: 19 AN: 294

European-Non Finnish (NFE) AF: 0.123 AC: 8382 AN: 68016

Other (OTH) AF: 0.135 AC: 285 AN: 2116

Alfa AF: 0.134 Hom.: 4343

Bravo AF: 0.154

Asia WGS AF: 0.0690 AC: 240 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.062
DANN	Benign	0.45
PhyloP100		-3.8
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3025382; hg19: chr9-136502321;