9-133646263-C-G

Variant names:

• chr9-133646263-C-G
• rs1541333
• NM_000787.4:c.1025-1583C>G

Variant summary

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

The NM_000787.4(DBH):​c.1025-1583C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.51 in 151,852 control chromosomes in the GnomAD database, including 20,658 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 0.51 (20658 hom., cov: 31)
• Consequence: DBH NM_000787.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0790
• Publications: 10 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=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.587 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.1025-1583C>G		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.1025-1583C>G		intron	N/A	ENSP00000376776.2	P09172
	DBH	ENST00000860939.1		c.1025-1583C>G		intron	N/A	ENSP00000530998.1

Frequencies

GnomAD3 genomes AF: 0.510 AC: 77402 AN: 151734 Hom.: 20635 Cov.: 31

Gnomad AFR AF: 0.593

Gnomad AMI AF: 0.330

Gnomad AMR AF: 0.387

Gnomad ASJ AF: 0.505

Gnomad EAS AF: 0.0898

Gnomad SAS AF: 0.335

Gnomad FIN AF: 0.443

Gnomad MID AF: 0.494

Gnomad NFE AF: 0.545

Gnomad OTH AF: 0.496

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

GnomAD4 genome AF: 0.510 AC: 77493 AN: 151852 Hom.: 20658 Cov.: 31 AF XY: 0.497 AC XY: 36830 AN XY: 74166

African (AFR) AF: 0.594 AC: 24542 AN: 41348

American (AMR) AF: 0.387 AC: 5913 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.505 AC: 1754 AN: 3470

East Asian (EAS) AF: 0.0900 AC: 466 AN: 5176

South Asian (SAS) AF: 0.337 AC: 1623 AN: 4812

European-Finnish (FIN) AF: 0.443 AC: 4656 AN: 10520

Middle Eastern (MID) AF: 0.500 AC: 147 AN: 294

European-Non Finnish (NFE) AF: 0.545 AC: 37042 AN: 67946

Other (OTH) AF: 0.498 AC: 1050 AN: 2108

Alfa AF: 0.415 Hom.: 1151

Bravo AF: 0.509

Asia WGS AF: 0.253 AC: 879 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	3.5
DANN	Benign	0.61
PhyloP100		0.079
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: rs1541333; hg19: chr9-136511385;