9-133652975-A-G

Variant names:

• chr9-133652975-A-G
• rs77905
• NM_000787.4:c.1410A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000787.4(DBH):​c.1410A>G​(p.Thr470Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.527 in 1,612,202 control chromosomes in the GnomAD database, including 229,337 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.55 (23211 hom., cov: 32)
  • Exomes 𝑓: 0.53 (206126 hom.)
• Consequence: DBH NM_000787.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.549
• Publications: 54 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 9-133652975-A-G is Benign according to our data. Variant chr9-133652975-A-G is described in ClinVar as Benign. ClinVar VariationId is 365661.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.549 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.88 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.1410A>G	p.Thr470Thr	synonymous	Exon 9 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.1410A>G	p.Thr470Thr	synonymous	Exon 9 of 12	ENSP00000376776.2

Frequencies

GnomAD3 genomes AF: 0.548 AC: 83153 AN: 151840 Hom.: 23203 Cov.: 32

Gnomad AFR AF: 0.570

Gnomad AMI AF: 0.696

Gnomad AMR AF: 0.609

Gnomad ASJ AF: 0.470

Gnomad EAS AF: 0.902

Gnomad SAS AF: 0.535

Gnomad FIN AF: 0.485

Gnomad MID AF: 0.579

Gnomad NFE AF: 0.507

Gnomad OTH AF: 0.515

GnomAD2 exomes AF: 0.566 AC: 142130 AN: 251046 AF XY: 0.557

Gnomad AFR exome AF: 0.582

Gnomad AMR exome AF: 0.695

Gnomad ASJ exome AF: 0.473

Gnomad EAS exome AF: 0.918

Gnomad FIN exome AF: 0.489

Gnomad NFE exome AF: 0.500

Gnomad OTH exome AF: 0.534

GnomAD4 exome AF: 0.525 AC: 766830 AN: 1460244 Hom.: 206126 Cov.: 40 AF XY: 0.525 AC XY: 381425 AN XY: 726482

African (AFR) AF: 0.576 AC: 19278 AN: 33464

American (AMR) AF: 0.686 AC: 30655 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.471 AC: 12307 AN: 26128

East Asian (EAS) AF: 0.905 AC: 35906 AN: 39694

South Asian (SAS) AF: 0.536 AC: 46190 AN: 86228

European-Finnish (FIN) AF: 0.482 AC: 25650 AN: 53168

Middle Eastern (MID) AF: 0.550 AC: 3164 AN: 5750

European-Non Finnish (NFE) AF: 0.506 AC: 561731 AN: 1110754

Other (OTH) AF: 0.529 AC: 31949 AN: 60352

GnomAD4 genome AF: 0.548 AC: 83206 AN: 151958 Hom.: 23211 Cov.: 32 AF XY: 0.549 AC XY: 40738 AN XY: 74264

African (AFR) AF: 0.570 AC: 23614 AN: 41440

American (AMR) AF: 0.609 AC: 9316 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.470 AC: 1629 AN: 3466

East Asian (EAS) AF: 0.902 AC: 4628 AN: 5130

South Asian (SAS) AF: 0.535 AC: 2583 AN: 4826

European-Finnish (FIN) AF: 0.485 AC: 5124 AN: 10562

Middle Eastern (MID) AF: 0.575 AC: 169 AN: 294

European-Non Finnish (NFE) AF: 0.507 AC: 34426 AN: 67924

Other (OTH) AF: 0.512 AC: 1082 AN: 2114

Alfa AF: 0.523 Hom.: 72621

Bravo AF: 0.563

Asia WGS AF: 0.673 AC: 2339 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Orthostatic hypotension 1 Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Jul 30, 2021

Genome-Nilou Lab

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	0.13
DANN	Benign	0.63
PhyloP100		-0.55
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: rs77905; hg19: chr9-136518097; COSMIC: COSV67548755; COSMIC: COSV67548755;