rs5320

chr9-133642351-G-A

Variant summary

Our verdict is Benign. Variant got -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. 13/19 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 Uncertain significance.

• 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:4
• Conservation: PhyloP100: -0.132

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 -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 id 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/exons	MANE	UniProt
DBH	NM_000787.4	c.631G>A	p.Ala211Thr	missense_variant	3/12	ENST00000393056.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DBH	ENST00000393056.8	c.631G>A	p.Ala211Thr	missense_variant	3/12	1	NM_000787.4	P1
DBH	ENST00000263611.3	c.478G>A	p.Ala160Thr	missense_variant	2/3	2

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

GnomAD3 exomes AF: 0.0674 AC: 16934 AN: 251274 Hom.: 716 AF XY: 0.0679 AC XY: 9227 AN XY: 135826

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 SAS exome AF: 0.0811

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

Gnomad4 AFR exome AF: 0.159

Gnomad4 AMR exome AF: 0.0427

Gnomad4 ASJ exome AF: 0.0835

Gnomad4 EAS exome AF: 0.121

Gnomad4 SAS exome AF: 0.0827

Gnomad4 FIN exome AF: 0.0544

Gnomad4 NFE exome AF: 0.0494

Gnomad4 OTH exome AF: 0.0668

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

Gnomad4 AFR AF: 0.153

Gnomad4 AMR AF: 0.0596

Gnomad4 ASJ AF: 0.0770

Gnomad4 EAS AF: 0.114

Gnomad4 SAS AF: 0.0799

Gnomad4 FIN AF: 0.0503

Gnomad4 NFE AF: 0.0531

Gnomad4 OTH AF: 0.0840

Alfa AF: 0.0634 Hom.: 910

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:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Orthostatic hypotension 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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	Invitae	Jan 30, 2024	- -

DBH-related condition Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 24, 2019

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

clinical testing

GeneDx

May 04, 2021

- -

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;.
MutationTaster	Benign	1.0	P
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

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: rs5320; hg19: chr9-136507473; COSMIC: COSV55041432;