rs1611131

Positions:

• chr9-133657065-A-G

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.1563-5A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.281 in 1,613,268 control chromosomes in the GnomAD database, including 67,034 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.26 (5520 hom., cov: 33)
  • Exomes 𝑓: 0.28 (61514 hom.)
• Consequence: DBH NM_000787.4 splice_region, intron
• Scores: Splicing: ADA: 0.000006447
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -3.56

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-AS1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 9-133657065-A-G is Benign according to our data. Variant chr9-133657065-A-G is described in ClinVar as [Benign]. Clinvar id is 365667.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-133657065-A-G is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.373 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DBH	NM_000787.4	c.1563-5A>G		splice_region_variant, intron_variant		ENST00000393056.8	NP_000778.3
DBH-AS1	NR_102735.1	n.282+62T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DBH	ENST00000393056.8	c.1563-5A>G		splice_region_variant, intron_variant		1	NM_000787.4	ENSP00000376776.2
DBH-AS1	ENST00000425189.1	n.187+62T>C		intron_variant		1

Frequencies

GnomAD3 genomes AF: 0.257 AC: 38991 AN: 151990 Hom.: 5521 Cov.: 33

Gnomad AFR AF: 0.138

Gnomad AMI AF: 0.422

Gnomad AMR AF: 0.327

Gnomad ASJ AF: 0.294

Gnomad EAS AF: 0.387

Gnomad SAS AF: 0.130

Gnomad FIN AF: 0.340

Gnomad MID AF: 0.285

Gnomad NFE AF: 0.294

Gnomad OTH AF: 0.269

GnomAD3 exomes AF: 0.284 AC: 71208 AN: 250752 Hom.: 11158 AF XY: 0.275 AC XY: 37307 AN XY: 135638

Gnomad AFR exome AF: 0.133

Gnomad AMR exome AF: 0.372

Gnomad ASJ exome AF: 0.286

Gnomad EAS exome AF: 0.412

Gnomad SAS exome AF: 0.129

Gnomad FIN exome AF: 0.342

Gnomad NFE exome AF: 0.288

Gnomad OTH exome AF: 0.295

GnomAD4 exome AF: 0.284 AC: 415076 AN: 1461160 Hom.: 61514 Cov.: 39 AF XY: 0.280 AC XY: 203216 AN XY: 726890

Gnomad4 AFR exome AF: 0.127

Gnomad4 AMR exome AF: 0.371

Gnomad4 ASJ exome AF: 0.291

Gnomad4 EAS exome AF: 0.411

Gnomad4 SAS exome AF: 0.130

Gnomad4 FIN exome AF: 0.333

Gnomad4 NFE exome AF: 0.291

Gnomad4 OTH exome AF: 0.274

GnomAD4 genome AF: 0.256 AC: 39006 AN: 152108 Hom.: 5520 Cov.: 33 AF XY: 0.257 AC XY: 19111 AN XY: 74364

Gnomad4 AFR AF: 0.138

Gnomad4 AMR AF: 0.327

Gnomad4 ASJ AF: 0.294

Gnomad4 EAS AF: 0.387

Gnomad4 SAS AF: 0.130

Gnomad4 FIN AF: 0.340

Gnomad4 NFE AF: 0.294

Gnomad4 OTH AF: 0.266

Alfa AF: 0.275 Hom.: 3909

Bravo AF: 0.255

Asia WGS AF: 0.243 AC: 845 AN: 3478

EpiCase AF: 0.283

EpiControl AF: 0.288

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	Genome-Nilou Lab	Jul 30, 2021	- -
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	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	-0.90
CADD	Benign	0.037
DANN	Benign	0.63
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0000064
dbscSNV1_RF	Benign	0.0020
SpliceAI score (max)		0.040		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: rs1611131; hg19: chr9-136522187; COSMIC: COSV67548958;