NM_000787.4:c.952G>T

Variant names:

• chr9-133644248-G-T
• rs4531
• NM_000787.4:c.952G>T

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.952G>T​(p.Ala318Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0776 in 1,613,524 control chromosomes in the GnomAD database, including 5,350 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.078 (536 hom., cov: 34)
  • Exomes 𝑓: 0.078 (4814 hom.)
• Consequence: DBH NM_000787.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.970
• Publications: 33 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=0.0028128922).
• BP6: Variant 9-133644248-G-T is Benign according to our data. Variant chr9-133644248-G-T is described in ClinVar as Benign. ClinVar VariationId is 365652.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.112 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000787.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DBH	NM_000787.4	MANE Select	c.952G>T	p.Ala318Ser	missense	Exon 5 of 12	NP_000778.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DBH	ENST00000393056.8	TSL:1 MANE Select	c.952G>T	p.Ala318Ser	missense	Exon 5 of 12	ENSP00000376776.2

Frequencies

GnomAD3 genomes AF: 0.0782 AC: 11898 AN: 152152 Hom.: 535 Cov.: 34

Gnomad AFR AF: 0.115

Gnomad AMI AF: 0.0362

Gnomad AMR AF: 0.0405

Gnomad ASJ AF: 0.0530

Gnomad EAS AF: 0.00519

Gnomad SAS AF: 0.0465

Gnomad FIN AF: 0.0438

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0797

Gnomad OTH AF: 0.0683

GnomAD2 exomes AF: 0.0632 AC: 15879 AN: 251432 AF XY: 0.0627

Gnomad AFR exome AF: 0.120

Gnomad AMR exome AF: 0.0338

Gnomad ASJ exome AF: 0.0540

Gnomad EAS exome AF: 0.00326

Gnomad FIN exome AF: 0.0468

Gnomad NFE exome AF: 0.0809

Gnomad OTH exome AF: 0.0668

GnomAD4 exome AF: 0.0775 AC: 113267 AN: 1461254 Hom.: 4814 Cov.: 33 AF XY: 0.0759 AC XY: 55167 AN XY: 726952

African (AFR) AF: 0.122 AC: 4073 AN: 33468

American (AMR) AF: 0.0352 AC: 1573 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0532 AC: 1391 AN: 26132

East Asian (EAS) AF: 0.00708 AC: 281 AN: 39700

South Asian (SAS) AF: 0.0490 AC: 4224 AN: 86250

European-Finnish (FIN) AF: 0.0495 AC: 2641 AN: 53398

Middle Eastern (MID) AF: 0.0444 AC: 256 AN: 5766

European-Non Finnish (NFE) AF: 0.0849 AC: 94347 AN: 1111438

Other (OTH) AF: 0.0742 AC: 4481 AN: 60378

GnomAD4 genome AF: 0.0782 AC: 11914 AN: 152270 Hom.: 536 Cov.: 34 AF XY: 0.0744 AC XY: 5537 AN XY: 74456

African (AFR) AF: 0.115 AC: 4779 AN: 41544

American (AMR) AF: 0.0405 AC: 619 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0530 AC: 184 AN: 3472

East Asian (EAS) AF: 0.00520 AC: 27 AN: 5190

South Asian (SAS) AF: 0.0469 AC: 226 AN: 4816

European-Finnish (FIN) AF: 0.0438 AC: 465 AN: 10616

Middle Eastern (MID) AF: 0.0544 AC: 16 AN: 294

European-Non Finnish (NFE) AF: 0.0797 AC: 5420 AN: 68008

Other (OTH) AF: 0.0685 AC: 145 AN: 2116

Alfa AF: 0.0759 Hom.: 1311

Bravo AF: 0.0809

TwinsUK AF: 0.0790 AC: 293

ALSPAC AF: 0.0893 AC: 344

ESP6500AA AF: 0.120 AC: 530

ESP6500EA AF: 0.0777 AC: 668

ExAC AF: 0.0665 AC: 8069

Asia WGS AF: 0.0470 AC: 164 AN: 3478

EpiCase AF: 0.0765

EpiControl AF: 0.0736

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Orthostatic hypotension 1 Benign:2

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.

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

Nov 20, 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 v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	2.7
DANN	Benign	0.85
DEOGEN2	Benign	0.10	T
Eigen	Benign	-0.99
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.60	D
LIST_S2	Benign	0.81	T
MetaRNN	Benign	0.0028	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L
PhyloP100		0.97
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.76	N
REVEL	Benign	0.062
Sift	Benign	0.24	T
Sift4G	Benign	0.26	T
Polyphen		0.067	B
Vest4		0.33
MPC		0.29
ClinPred		0.012	T
GERP RS		-0.85
Varity_R		0.17
gMVP		0.74
Mutation Taster		=92/8	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs4531; hg19: chr9-136509370; COSMIC: COSV55040352; COSMIC: COSV55040352;