rs129882

Positions:

• chr9-133658547-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000393056.8(DBH):​c.*100C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.202 in 1,336,366 control chromosomes in the GnomAD database, including 28,781 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3316 hom., cov: 32)
  • Exomes 𝑓: 0.20 (25465 hom.)
• Consequence: DBH ENST00000393056.8 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.0780

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 (BayesDel_noAF=-0.77).
• BP6: Variant 9-133658547-C-T is Benign according to our data. Variant chr9-133658547-C-T is described in ClinVar as [Benign]. Clinvar id is 365678.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-133658547-C-T is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.364 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DBH	NM_000787.4	c.*100C>T		3_prime_UTR_variant	12/12	ENST00000393056.8	NP_000778.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DBH	ENST00000393056.8	c.*100C>T		3_prime_UTR_variant	12/12	1	NM_000787.4	ENSP00000376776	P1

Frequencies

GnomAD3 genomes AF: 0.203 AC: 30844 AN: 152080 Hom.: 3319 Cov.: 32

Gnomad AFR AF: 0.199

Gnomad AMI AF: 0.0868

Gnomad AMR AF: 0.226

Gnomad ASJ AF: 0.189

Gnomad EAS AF: 0.377

Gnomad SAS AF: 0.310

Gnomad FIN AF: 0.149

Gnomad MID AF: 0.215

Gnomad NFE AF: 0.189

Gnomad OTH AF: 0.201

GnomAD4 exome AF: 0.202 AC: 238629 AN: 1184168 Hom.: 25465 Cov.: 16 AF XY: 0.204 AC XY: 117499 AN XY: 576088

Gnomad4 AFR exome AF: 0.193

Gnomad4 AMR exome AF: 0.262

Gnomad4 ASJ exome AF: 0.196

Gnomad4 EAS exome AF: 0.390

Gnomad4 SAS exome AF: 0.299

Gnomad4 FIN exome AF: 0.156

Gnomad4 NFE exome AF: 0.190

Gnomad4 OTH exome AF: 0.211

GnomAD4 genome AF: 0.203 AC: 30860 AN: 152198 Hom.: 3316 Cov.: 32 AF XY: 0.205 AC XY: 15277 AN XY: 74434

Gnomad4 AFR AF: 0.199

Gnomad4 AMR AF: 0.226

Gnomad4 ASJ AF: 0.189

Gnomad4 EAS AF: 0.378

Gnomad4 SAS AF: 0.309

Gnomad4 FIN AF: 0.149

Gnomad4 NFE AF: 0.189

Gnomad4 OTH AF: 0.199

Alfa AF: 0.190 Hom.: 2778

Bravo AF: 0.207

Asia WGS AF: 0.321 AC: 1118 AN: 3478

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	Labcorp Genetics (formerly Invitae), Labcorp	Nov 27, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 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. -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 11, 2021	This variant is associated with the following publications: (PMID: 25975715, 20498626) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	6.2
DANN	Benign	0.78

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: rs129882; hg19: chr9-136523669; COSMIC: COSV67549685; COSMIC: COSV67549685;