rs45446891

Variant names:

• chr9-133658327-C-T
• rs45446891
• NM_000787.4:c.1734C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000787.4(DBH):​c.1734C>T​(p.Asn578Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0163 in 1,613,902 control chromosomes in the GnomAD database, including 258 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (17 hom., cov: 32)
  • Exomes 𝑓: 0.017 (241 hom.)
• Consequence: DBH NM_000787.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.868
• Publications: 6 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 9-133658327-C-T is Benign according to our data. Variant chr9-133658327-C-T is described in ClinVar as Benign. ClinVar VariationId is 365673.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.868 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0126 (1924/152246) while in subpopulation NFE AF = 0.0178 (1209/67996). AF 95% confidence interval is 0.0169. There are 17 homozygotes in GnomAd4. There are 933 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 17 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DBH	NM_000787.4	c.1734C>T	p.Asn578Asn	synonymous_variant	Exon 12 of 12	ENST00000393056.8	NP_000778.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DBH	ENST00000393056.8	c.1734C>T	p.Asn578Asn	synonymous_variant	Exon 12 of 12	1	NM_000787.4	ENSP00000376776.2

Frequencies

GnomAD3 genomes AF: 0.0126 AC: 1924 AN: 152128 Hom.: 17 Cov.: 32

Gnomad AFR AF: 0.00364

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00877

Gnomad ASJ AF: 0.0397

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0122

Gnomad FIN AF: 0.0180

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0178

Gnomad OTH AF: 0.0144

GnomAD2 exomes AF: 0.0157 AC: 3899 AN: 248846 AF XY: 0.0164

Gnomad AFR exome AF: 0.00252

Gnomad AMR exome AF: 0.00487

Gnomad ASJ exome AF: 0.0446

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0176

Gnomad NFE exome AF: 0.0203

Gnomad OTH exome AF: 0.0185

GnomAD4 exome AF: 0.0167 AC: 24356 AN: 1461656 Hom.: 241 Cov.: 31 AF XY: 0.0169 AC XY: 12287 AN XY: 727152

African (AFR) AF: 0.00281 AC: 94 AN: 33478

American (AMR) AF: 0.00555 AC: 248 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.0439 AC: 1147 AN: 26122

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39696

South Asian (SAS) AF: 0.0171 AC: 1475 AN: 86242

European-Finnish (FIN) AF: 0.0187 AC: 998 AN: 53394

Middle Eastern (MID) AF: 0.0370 AC: 213 AN: 5764

European-Non Finnish (NFE) AF: 0.0173 AC: 19203 AN: 1111862

Other (OTH) AF: 0.0162 AC: 977 AN: 60388

GnomAD4 genome AF: 0.0126 AC: 1924 AN: 152246 Hom.: 17 Cov.: 32 AF XY: 0.0125 AC XY: 933 AN XY: 74430

African (AFR) AF: 0.00363 AC: 151 AN: 41560

American (AMR) AF: 0.00875 AC: 134 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0397 AC: 138 AN: 3472

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5164

South Asian (SAS) AF: 0.0125 AC: 60 AN: 4818

European-Finnish (FIN) AF: 0.0180 AC: 191 AN: 10614

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0178 AC: 1209 AN: 67996

Other (OTH) AF: 0.0142 AC: 30 AN: 2108

Alfa AF: 0.0165 Hom.: 15

Bravo AF: 0.0115

Asia WGS AF: 0.00664 AC: 23 AN: 3478

EpiCase AF: 0.0168

EpiControl AF: 0.0188

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Orthostatic hypotension 1 Benign:2

Jan 30, 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. -

DBH-related disorder Benign:1

Jan 13, 2020

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	0.12
DANN	Benign	0.64
PhyloP100		-0.87
Mutation Taster		=100/0	polymorphism

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: rs45446891; hg19: chr9-136523449;