9-133639801-C-T

Variant names:

• chr9-133639801-C-T
• rs1611118
• NM_000787.4:c.340-45C>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.340-45C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0583 in 1,589,308 control chromosomes in the GnomAD database, including 3,026 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.045 (178 hom., cov: 33)
  • Exomes 𝑓: 0.060 (2848 hom.)
• Consequence: DBH NM_000787.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.65
• Publications: 10 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 (BayesDel_noAF=-0.87).
• BP6: Variant 9-133639801-C-T is Benign according to our data. Variant chr9-133639801-C-T is described in ClinVar as Benign. ClinVar VariationId is 1235638.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0614 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.340-45C>T		intron	N/A	NP_000778.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DBH	ENST00000393056.8	TSL:1 MANE Select	c.340-45C>T		intron	N/A	ENSP00000376776.2
	DBH	ENST00000263611.3	TSL:2	c.334-2406C>T		intron	N/A	ENSP00000263611.3

Frequencies

GnomAD3 genomes AF: 0.0446 AC: 6791 AN: 152170 Hom.: 177 Cov.: 33

Gnomad AFR AF: 0.0168

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.0416

Gnomad ASJ AF: 0.0668

Gnomad EAS AF: 0.0197

Gnomad SAS AF: 0.0277

Gnomad FIN AF: 0.0544

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0630

Gnomad OTH AF: 0.0556

GnomAD2 exomes AF: 0.0481 AC: 10346 AN: 215054 AF XY: 0.0485

Gnomad AFR exome AF: 0.0160

Gnomad AMR exome AF: 0.0285

Gnomad ASJ exome AF: 0.0724

Gnomad EAS exome AF: 0.0222

Gnomad FIN exome AF: 0.0551

Gnomad NFE exome AF: 0.0639

Gnomad OTH exome AF: 0.0568

GnomAD4 exome AF: 0.0597 AC: 85862 AN: 1437020 Hom.: 2848 Cov.: 31 AF XY: 0.0589 AC XY: 42012 AN XY: 713024

African (AFR) AF: 0.0153 AC: 507 AN: 33178

American (AMR) AF: 0.0288 AC: 1208 AN: 41888

Ashkenazi Jewish (ASJ) AF: 0.0718 AC: 1840 AN: 25642

East Asian (EAS) AF: 0.0164 AC: 643 AN: 39146

South Asian (SAS) AF: 0.0349 AC: 2912 AN: 83516

European-Finnish (FIN) AF: 0.0574 AC: 2789 AN: 48628

Middle Eastern (MID) AF: 0.0418 AC: 184 AN: 4400

European-Non Finnish (NFE) AF: 0.0659 AC: 72611 AN: 1101194

Other (OTH) AF: 0.0533 AC: 3168 AN: 59428

GnomAD4 genome AF: 0.0446 AC: 6792 AN: 152288 Hom.: 178 Cov.: 33 AF XY: 0.0437 AC XY: 3256 AN XY: 74454

African (AFR) AF: 0.0168 AC: 697 AN: 41566

American (AMR) AF: 0.0415 AC: 635 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0668 AC: 232 AN: 3472

East Asian (EAS) AF: 0.0199 AC: 103 AN: 5178

South Asian (SAS) AF: 0.0284 AC: 137 AN: 4826

European-Finnish (FIN) AF: 0.0544 AC: 577 AN: 10614

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.0630 AC: 4284 AN: 68018

Other (OTH) AF: 0.0545 AC: 115 AN: 2110

Alfa AF: 0.0579 Hom.: 238

Bravo AF: 0.0419

Asia WGS AF: 0.0170 AC: 59 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

May 16, 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	-0.87
CADD	Benign	0.086
DANN	Benign	0.66
PhyloP100		-2.6
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1611118; hg19: chr9-136504923; COSMIC: COSV55041902;