9-133650175-C-T

Variant names:

• chr9-133650175-C-T
• rs2283123
• NM_000787.4:c.1192-1459C>T

Variant summary

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

The NM_000787.4(DBH):​c.1192-1459C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0975 in 152,194 control chromosomes in the GnomAD database, including 778 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 0.097 (778 hom., cov: 32)
• Consequence: DBH NM_000787.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.314
• Publications: 8 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=-0.94).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.176 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DBH	NM_000787.4	c.1192-1459C>T		intron_variant	Intron 6 of 11	ENST00000393056.8	NP_000778.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DBH	ENST00000393056.8	c.1192-1459C>T		intron_variant	Intron 6 of 11	1	NM_000787.4	ENSP00000376776.2

Frequencies

GnomAD3 genomes AF: 0.0975 AC: 14828 AN: 152076 Hom.: 777 Cov.: 32

Gnomad AFR AF: 0.0777

Gnomad AMI AF: 0.181

Gnomad AMR AF: 0.0648

Gnomad ASJ AF: 0.0772

Gnomad EAS AF: 0.129

Gnomad SAS AF: 0.186

Gnomad FIN AF: 0.0714

Gnomad MID AF: 0.104

Gnomad NFE AF: 0.113

Gnomad OTH AF: 0.0840

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

GnomAD4 genome AF: 0.0975 AC: 14836 AN: 152194 Hom.: 778 Cov.: 32 AF XY: 0.0969 AC XY: 7207 AN XY: 74414

African (AFR) AF: 0.0777 AC: 3227 AN: 41550

American (AMR) AF: 0.0646 AC: 989 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0772 AC: 268 AN: 3470

East Asian (EAS) AF: 0.130 AC: 669 AN: 5158

South Asian (SAS) AF: 0.187 AC: 898 AN: 4814

European-Finnish (FIN) AF: 0.0714 AC: 757 AN: 10598

Middle Eastern (MID) AF: 0.105 AC: 31 AN: 294

European-Non Finnish (NFE) AF: 0.113 AC: 7654 AN: 67986

Other (OTH) AF: 0.0841 AC: 178 AN: 2116

Alfa AF: 0.101 Hom.: 1389

Bravo AF: 0.0945

Asia WGS AF: 0.150 AC: 524 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	1.7
DANN	Benign	0.50
PhyloP100		-0.31
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: rs2283123; hg19: chr9-136515297;