rs5320

Variant names:

• chr9-133642351-G-A
• rs5320
• NM_000787.4:c.631G>A

Your query was ambiguous. Multiple possible variants found:

• chr9-133642351-G-A
• chr9-133642351-G-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000787.4(DBH):​c.631G>A​(p.Ala211Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0599 in 1,613,986 control chromosomes in the GnomAD database, including 3,671 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A211V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.085 (691 hom., cov: 32)
  • Exomes 𝑓: 0.057 (2980 hom.)
• Consequence: DBH NM_000787.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.132
• Publications: 39 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0016213655).
• BP6: Variant 9-133642351-G-A is Benign according to our data. Variant chr9-133642351-G-A is described in ClinVar as Benign. ClinVar VariationId is 365641.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.15 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DBH	NM_000787.4	c.631G>A	p.Ala211Thr	missense_variant	Exon 3 of 12	ENST00000393056.8	NP_000778.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DBH	ENST00000393056.8	c.631G>A	p.Ala211Thr	missense_variant	Exon 3 of 12	1	NM_000787.4	ENSP00000376776.2
DBH	ENST00000263611.3	c.478G>A	p.Ala160Thr	missense_variant	Exon 2 of 3	2		ENSP00000263611.3

Frequencies

GnomAD3 genomes AF: 0.0845 AC: 12848 AN: 152018 Hom.: 684 Cov.: 32

Gnomad AFR AF: 0.153

Gnomad AMI AF: 0.0384

Gnomad AMR AF: 0.0595

Gnomad ASJ AF: 0.0770

Gnomad EAS AF: 0.114

Gnomad SAS AF: 0.0798

Gnomad FIN AF: 0.0503

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.0531

Gnomad OTH AF: 0.0767

GnomAD2 exomes AF: 0.0674 AC: 16934 AN: 251274 AF XY: 0.0679

Gnomad AFR exome AF: 0.152

Gnomad AMR exome AF: 0.0391

Gnomad ASJ exome AF: 0.0811

Gnomad EAS exome AF: 0.112

Gnomad FIN exome AF: 0.0535

Gnomad NFE exome AF: 0.0547

Gnomad OTH exome AF: 0.0623

GnomAD4 exome AF: 0.0573 AC: 83728 AN: 1461850 Hom.: 2980 Cov.: 33 AF XY: 0.0580 AC XY: 42190 AN XY: 727226

African (AFR) AF: 0.159 AC: 5323 AN: 33478

American (AMR) AF: 0.0427 AC: 1909 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0835 AC: 2182 AN: 26136

East Asian (EAS) AF: 0.121 AC: 4807 AN: 39696

South Asian (SAS) AF: 0.0827 AC: 7136 AN: 86258

European-Finnish (FIN) AF: 0.0544 AC: 2908 AN: 53410

Middle Eastern (MID) AF: 0.0860 AC: 496 AN: 5768

European-Non Finnish (NFE) AF: 0.0494 AC: 54934 AN: 1111990

Other (OTH) AF: 0.0668 AC: 4033 AN: 60396

GnomAD4 genome AF: 0.0847 AC: 12882 AN: 152136 Hom.: 691 Cov.: 32 AF XY: 0.0839 AC XY: 6240 AN XY: 74378

African (AFR) AF: 0.153 AC: 6359 AN: 41484

American (AMR) AF: 0.0596 AC: 911 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0770 AC: 267 AN: 3466

East Asian (EAS) AF: 0.114 AC: 587 AN: 5166

South Asian (SAS) AF: 0.0799 AC: 385 AN: 4820

European-Finnish (FIN) AF: 0.0503 AC: 533 AN: 10604

Middle Eastern (MID) AF: 0.0612 AC: 18 AN: 294

European-Non Finnish (NFE) AF: 0.0531 AC: 3610 AN: 67988

Other (OTH) AF: 0.0840 AC: 177 AN: 2108

Alfa AF: 0.0671 Hom.: 1480

Bravo AF: 0.0890

TwinsUK AF: 0.0529 AC: 196

ALSPAC AF: 0.0493 AC: 190

ESP6500AA AF: 0.144 AC: 635

ESP6500EA AF: 0.0560 AC: 482

ExAC AF: 0.0693 AC: 8415

Asia WGS AF: 0.108 AC: 375 AN: 3478

EpiCase AF: 0.0587

EpiControl AF: 0.0576

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Orthostatic hypotension 1 Benign:2

Jan 13, 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. -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 04, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

DBH-related disorder Benign:1

Oct 24, 2019

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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	0.034
DANN	Benign	0.70
DEOGEN2	Benign	0.15	T;.
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.020	N
LIST_S2	Benign	0.45	T;T
MetaRNN	Benign	0.0016	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.065	N;.
PhyloP100		-0.13
PrimateAI	Benign	0.24	T
PROVEAN	Benign	0.97	N;.
REVEL	Benign	0.023
Sift	Benign	0.77	T;.
Sift4G	Benign	0.68	T;.
Polyphen		0.0	B;.
Vest4		0.011
MPC		0.055
ClinPred		0.0040	T
GERP RS		-4.7
Varity_R		0.092
gMVP		0.28
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: rs5320; hg19: chr9-136507473; COSMIC: COSV55041432;