rs1611131

Variant names:

• chr9-133657065-A-G
• rs1611131
• NM_000787.4:c.1563-5A>G

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.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
• Publications: 23 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-AS1 (HGNC:24155): (DBH antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 365667.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.373 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.1563-5A>G		splice_region intron	N/A	NP_000778.3
	DBH-AS1	NR_102735.1		n.282+62T>C		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DBH	ENST00000393056.8	TSL:1 MANE Select	c.1563-5A>G		splice_region intron	N/A	ENSP00000376776.2
	DBH-AS1	ENST00000425189.1	TSL:1	n.187+62T>C		intron	N/A
	DBH	ENST00000860939.1		c.1563-5A>G		splice_region intron	N/A	ENSP00000530998.1

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

GnomAD2 exomes AF: 0.284 AC: 71208 AN: 250752 AF XY: 0.275

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 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

African (AFR) AF: 0.127 AC: 4251 AN: 33474

American (AMR) AF: 0.371 AC: 16581 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.291 AC: 7611 AN: 26132

East Asian (EAS) AF: 0.411 AC: 16314 AN: 39686

South Asian (SAS) AF: 0.130 AC: 11242 AN: 86252

European-Finnish (FIN) AF: 0.333 AC: 17664 AN: 53006

Middle Eastern (MID) AF: 0.300 AC: 1728 AN: 5768

European-Non Finnish (NFE) AF: 0.291 AC: 323123 AN: 1111740

Other (OTH) AF: 0.274 AC: 16562 AN: 60384

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

African (AFR) AF: 0.138 AC: 5739 AN: 41498

American (AMR) AF: 0.327 AC: 5004 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.294 AC: 1022 AN: 3472

East Asian (EAS) AF: 0.387 AC: 1995 AN: 5158

South Asian (SAS) AF: 0.130 AC: 626 AN: 4814

European-Finnish (FIN) AF: 0.340 AC: 3599 AN: 10590

Middle Eastern (MID) AF: 0.282 AC: 83 AN: 294

European-Non Finnish (NFE) AF: 0.294 AC: 19993 AN: 67974

Other (OTH) AF: 0.266 AC: 560 AN: 2104

Alfa AF: 0.274 Hom.: 13049

Bravo AF: 0.255

Asia WGS AF: 0.243 AC: 845 AN: 3478

EpiCase AF: 0.283

EpiControl AF: 0.288

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.037
DANN	Benign	0.63
PhyloP100		-3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1611131; hg19: chr9-136522187; COSMIC: COSV67548958;