rs45446891

chr9-133658327-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000787.4(DBH):c.1734C>T(p.Asn578=) 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:3
• Conservation: PhyloP100: -0.868

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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 male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 17 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DBH	NM_000787.4	c.1734C>T	p.Asn578=	synonymous_variant	12/12	ENST00000393056.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DBH	ENST00000393056.8	c.1734C>T	p.Asn578=	synonymous_variant	12/12	1	NM_000787.4	P1

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

GnomAD3 exomes AF: 0.0157 AC: 3899 AN: 248846 Hom.: 32 AF XY: 0.0164 AC XY: 2204 AN XY: 134772

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 SAS exome AF: 0.0161

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

Gnomad4 AFR exome AF: 0.00281

Gnomad4 AMR exome AF: 0.00555

Gnomad4 ASJ exome AF: 0.0439

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0171

Gnomad4 FIN exome AF: 0.0187

Gnomad4 NFE exome AF: 0.0173

Gnomad4 OTH exome AF: 0.0162

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

Gnomad4 AFR AF: 0.00363

Gnomad4 AMR AF: 0.00875

Gnomad4 ASJ AF: 0.0397

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.0125

Gnomad4 FIN AF: 0.0180

Gnomad4 NFE AF: 0.0178

Gnomad4 OTH AF: 0.0142

Alfa AF: 0.0192 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:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Orthostatic hypotension 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 13, 2020

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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
Cadd	Benign	0.12
Dann	Benign	0.64

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

Publications

LitVar

Other links and lift over

dbSNP: rs45446891; hg19: chr9-136523449;