9-133639992-A-G

Variant names:

• chr9-133639992-A-G
• rs1108580
• NM_000787.4:c.486A>G

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_000787.4(DBH):​c.486A>G​(p.Glu162Glu) variant causes a splice region, synonymous change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.516 in 1,612,950 control chromosomes in the GnomAD database, including 223,425 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 0.53 (22686 hom., cov: 33)
  • Exomes 𝑓: 0.51 (200739 hom.)
• Consequence: DBH NM_000787.4 splice_region, synonymous
• Scores: Splicing: ADA: 0.0003180
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 7.51
• Publications: 81 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: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.38).
• BP6: Variant 9-133639992-A-G is Benign according to our data. Variant chr9-133639992-A-G is described in ClinVar as Benign. ClinVar VariationId is 217758.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.66 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DBH	NM_000787.4	MANE Select	c.486A>G	p.Glu162Glu	splice_region synonymous	Exon 2 of 12	NP_000778.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DBH	ENST00000393056.8	TSL:1 MANE Select	c.486A>G	p.Glu162Glu	splice_region synonymous	Exon 2 of 12	ENSP00000376776.2	P09172
	DBH	ENST00000860939.1		c.486A>G	p.Glu162Glu	splice_region synonymous	Exon 2 of 12	ENSP00000530998.1
	DBH	ENST00000263611.3	TSL:2	c.334-2215A>G		intron	N/A	ENSP00000263611.3	Q5T382

Frequencies

GnomAD3 genomes AF: 0.532 AC: 80884 AN: 151944 Hom.: 22649 Cov.: 33

Gnomad AFR AF: 0.666

Gnomad AMI AF: 0.337

Gnomad AMR AF: 0.397

Gnomad ASJ AF: 0.454

Gnomad EAS AF: 0.132

Gnomad SAS AF: 0.328

Gnomad FIN AF: 0.491

Gnomad MID AF: 0.456

Gnomad NFE AF: 0.541

Gnomad OTH AF: 0.505

GnomAD2 exomes AF: 0.449 AC: 112158 AN: 249648 AF XY: 0.450

Gnomad AFR exome AF: 0.661

Gnomad AMR exome AF: 0.285

Gnomad ASJ exome AF: 0.461

Gnomad EAS exome AF: 0.126

Gnomad FIN exome AF: 0.498

Gnomad NFE exome AF: 0.538

Gnomad OTH exome AF: 0.467

GnomAD4 exome AF: 0.515 AC: 751787 AN: 1460888 Hom.: 200739 Cov.: 55 AF XY: 0.509 AC XY: 370059 AN XY: 726730

African (AFR) AF: 0.673 AC: 22517 AN: 33474

American (AMR) AF: 0.299 AC: 13340 AN: 44648

Ashkenazi Jewish (ASJ) AF: 0.462 AC: 12077 AN: 26124

East Asian (EAS) AF: 0.134 AC: 5302 AN: 39692

South Asian (SAS) AF: 0.354 AC: 30544 AN: 86190

European-Finnish (FIN) AF: 0.505 AC: 26798 AN: 53054

Middle Eastern (MID) AF: 0.436 AC: 2510 AN: 5760

European-Non Finnish (NFE) AF: 0.548 AC: 609154 AN: 1111590

Other (OTH) AF: 0.490 AC: 29545 AN: 60356

GnomAD4 genome AF: 0.533 AC: 80984 AN: 152062 Hom.: 22686 Cov.: 33 AF XY: 0.521 AC XY: 38702 AN XY: 74312

African (AFR) AF: 0.666 AC: 27649 AN: 41500

American (AMR) AF: 0.397 AC: 6060 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.454 AC: 1574 AN: 3470

East Asian (EAS) AF: 0.132 AC: 679 AN: 5156

South Asian (SAS) AF: 0.328 AC: 1584 AN: 4822

European-Finnish (FIN) AF: 0.491 AC: 5183 AN: 10554

Middle Eastern (MID) AF: 0.476 AC: 140 AN: 294

European-Non Finnish (NFE) AF: 0.541 AC: 36737 AN: 67960

Other (OTH) AF: 0.507 AC: 1072 AN: 2116

Alfa AF: 0.529 Hom.: 82497

Bravo AF: 0.529

Asia WGS AF: 0.275 AC: 956 AN: 3478

EpiCase AF: 0.535

EpiControl AF: 0.525

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Orthostatic hypotension 1 (3)
-	-	2	not provided (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Benign	13
DANN	Benign	0.84
PhyloP100		7.5
Mutation Taster		=7/93	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00032
dbscSNV1_RF	Benign	0.020
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: rs1108580; hg19: chr9-136505114; COSMIC: COSV55040789;