NM_000787.4:c.486+127A>G

Variant names:

• chr9-133640119-A-G
• rs1108581
• NM_000787.4:c.486+127A>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.486+127A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.205 in 1,295,830 control chromosomes in the GnomAD database, including 30,119 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.26 (6092 hom., cov: 33)
  • Exomes 𝑓: 0.20 (24027 hom.)
• Consequence: DBH NM_000787.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.193
• Publications: 20 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=-0.92).
• BP6: Variant 9-133640119-A-G is Benign according to our data. Variant chr9-133640119-A-G is described in ClinVar as Benign. ClinVar VariationId is 1258192.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.438 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.486+127A>G		intron	N/A	NP_000778.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DBH	ENST00000393056.8	TSL:1 MANE Select	c.486+127A>G		intron	N/A	ENSP00000376776.2
	DBH	ENST00000860939.1		c.486+127A>G		intron	N/A	ENSP00000530998.1
	DBH	ENST00000263611.3	TSL:2	c.334-2088A>G		intron	N/A	ENSP00000263611.3

Frequencies

GnomAD3 genomes AF: 0.259 AC: 39432 AN: 152086 Hom.: 6069 Cov.: 33

Gnomad AFR AF: 0.443

Gnomad AMI AF: 0.106

Gnomad AMR AF: 0.160

Gnomad ASJ AF: 0.209

Gnomad EAS AF: 0.141

Gnomad SAS AF: 0.176

Gnomad FIN AF: 0.179

Gnomad MID AF: 0.158

Gnomad NFE AF: 0.203

Gnomad OTH AF: 0.229

GnomAD4 exome AF: 0.198 AC: 226223 AN: 1143626 Hom.: 24027 AF XY: 0.197 AC XY: 113094 AN XY: 575106

African (AFR) AF: 0.447 AC: 11992 AN: 26838

American (AMR) AF: 0.118 AC: 4305 AN: 36426

Ashkenazi Jewish (ASJ) AF: 0.216 AC: 5045 AN: 23342

East Asian (EAS) AF: 0.144 AC: 5145 AN: 35740

South Asian (SAS) AF: 0.189 AC: 14119 AN: 74622

European-Finnish (FIN) AF: 0.181 AC: 6763 AN: 37304

Middle Eastern (MID) AF: 0.192 AC: 958 AN: 4986

European-Non Finnish (NFE) AF: 0.196 AC: 167710 AN: 854428

Other (OTH) AF: 0.204 AC: 10186 AN: 49940

GnomAD4 genome AF: 0.260 AC: 39502 AN: 152204 Hom.: 6092 Cov.: 33 AF XY: 0.254 AC XY: 18871 AN XY: 74414

African (AFR) AF: 0.443 AC: 18394 AN: 41524

American (AMR) AF: 0.160 AC: 2450 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.209 AC: 724 AN: 3472

East Asian (EAS) AF: 0.141 AC: 728 AN: 5178

South Asian (SAS) AF: 0.177 AC: 852 AN: 4824

European-Finnish (FIN) AF: 0.179 AC: 1897 AN: 10600

Middle Eastern (MID) AF: 0.167 AC: 49 AN: 294

European-Non Finnish (NFE) AF: 0.203 AC: 13814 AN: 67988

Other (OTH) AF: 0.236 AC: 497 AN: 2110

Alfa AF: 0.229 Hom.: 9327

Bravo AF: 0.266

Asia WGS AF: 0.195 AC: 680 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	2.6
DANN	Benign	0.68
PhyloP100		0.19
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1108581; hg19: chr9-136505241; COSMIC: COSV55042819;