rs45446891

Positions:

chr9-133658327-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.868

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 17 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DBH	NM_000787.4 link	c.1734C>T	p.Asn578Asn	synonymous_variant	12/12	ENST00000393056.8	NP_000778.3	P09172

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DBH	ENST00000393056.8 link	c.1734C>T	p.Asn578Asn	synonymous_variant	12/12	1	NM_000787.4	ENSP00000376776.2		P09172

Frequencies

GnomAD3 genomes

AF:

0.0126

AC:

1924

AN:

152128

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.0164

AC XY:

2204

AN XY:

134772

show subpopulations

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.:

AF XY:

0.0169

AC XY:

12287

AN XY:

727152

show subpopulations

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.:

Cov.:

AF XY:

0.0125

AC XY:

933

AN XY:

74430

show subpopulations

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.:

Bravo

AF:

0.0115

Asia WGS

AF:

0.00664

AC:

AN:

3478

EpiCase

AF:

0.0168

EpiControl

AF:

0.0188

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Orthostatic hypotension 1

Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

DBH-related disorder

Benign:1

Benign, no assertion criteria provided

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). -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over