NM_000787.4:c.486+530T>C

Variant names:

• chr9-133640522-T-C
• rs2873804
• NM_000787.4:c.486+530T>C

Variant summary

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

The NM_000787.4(DBH):​c.486+530T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.523 in 152,116 control chromosomes in the GnomAD database, including 21,889 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 0.52 (21889 hom., cov: 33)
• Consequence: DBH NM_000787.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.40
• Publications: 16 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: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.99).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.646 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DBH	NM_000787.4	MANE Select	c.486+530T>C		intron	N/A	NP_000778.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DBH	ENST00000393056.8	TSL:1 MANE Select	c.486+530T>C		intron	N/A	ENSP00000376776.2	P09172
	DBH	ENST00000860939.1		c.486+530T>C		intron	N/A	ENSP00000530998.1
	DBH	ENST00000263611.3	TSL:2	c.334-1685T>C		intron	N/A	ENSP00000263611.3	Q5T382

Frequencies

GnomAD3 genomes AF: 0.523 AC: 79523 AN: 151998 Hom.: 21851 Cov.: 33

Gnomad AFR AF: 0.652

Gnomad AMI AF: 0.328

Gnomad AMR AF: 0.389

Gnomad ASJ AF: 0.435

Gnomad EAS AF: 0.142

Gnomad SAS AF: 0.303

Gnomad FIN AF: 0.481

Gnomad MID AF: 0.440

Gnomad NFE AF: 0.534

Gnomad OTH AF: 0.500

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

GnomAD4 genome AF: 0.523 AC: 79627 AN: 152116 Hom.: 21889 Cov.: 33 AF XY: 0.512 AC XY: 38063 AN XY: 74384

African (AFR) AF: 0.653 AC: 27074 AN: 41482

American (AMR) AF: 0.389 AC: 5953 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.435 AC: 1510 AN: 3468

East Asian (EAS) AF: 0.142 AC: 734 AN: 5182

South Asian (SAS) AF: 0.304 AC: 1467 AN: 4824

European-Finnish (FIN) AF: 0.481 AC: 5094 AN: 10584

Middle Eastern (MID) AF: 0.452 AC: 133 AN: 294

European-Non Finnish (NFE) AF: 0.534 AC: 36307 AN: 67982

Other (OTH) AF: 0.502 AC: 1056 AN: 2104

Alfa AF: 0.522 Hom.: 61117

Bravo AF: 0.521

Asia WGS AF: 0.267 AC: 930 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	0.15
DANN	Benign	0.54
PhyloP100		-2.4
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: rs2873804; hg19: chr9-136505644;