9-133652975-A-G

Position:

• chr9-133652975-A-G

Variant summary

Our verdict is Benign. Variant got -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

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 -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 id is 365661.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-133652975-A-G is described in Lovd as [Benign].
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DBH	NM_000787.4	c.1410A>G	p.Thr470Thr	synonymous_variant	9/12	ENST00000393056.8	NP_000778.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DBH	ENST00000393056.8	c.1410A>G	p.Thr470Thr	synonymous_variant	9/12	1	NM_000787.4	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

GnomAD3 exomes AF: 0.566 AC: 142130 AN: 251046 Hom.: 42410 AF XY: 0.557 AC XY: 75643 AN XY: 135772

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 SAS exome AF: 0.536

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

Gnomad4 AFR exome AF: 0.576

Gnomad4 AMR exome AF: 0.686

Gnomad4 ASJ exome AF: 0.471

Gnomad4 EAS exome AF: 0.905

Gnomad4 SAS exome AF: 0.536

Gnomad4 FIN exome AF: 0.482

Gnomad4 NFE exome AF: 0.506

Gnomad4 OTH exome AF: 0.529

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

Gnomad4 AFR AF: 0.570

Gnomad4 AMR AF: 0.609

Gnomad4 ASJ AF: 0.470

Gnomad4 EAS AF: 0.902

Gnomad4 SAS AF: 0.535

Gnomad4 FIN AF: 0.485

Gnomad4 NFE AF: 0.507

Gnomad4 OTH AF: 0.512

Alfa AF: 0.517 Hom.: 34575

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

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	Genome-Nilou Lab	Jul 30, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	- -
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	-0.58
CADD	Benign	0.13
DANN	Benign	0.63

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: rs77905; hg19: chr9-136518097; COSMIC: COSV67548755; COSMIC: COSV67548755;