9-133652975-A-G

Variant names:

• chr9-133652975-A-G
• rs77905
• NM_000787.4:c.1410A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000787.4(DBH):​c.1410A>G​(p.Thr470Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.527 in 1,612,202 control chromosomes in the GnomAD database, including 229,337 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.55 (23211 hom., cov: 32)
  • Exomes 𝑓: 0.53 (206126 hom.)
• Consequence: DBH NM_000787.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.549
• Publications: 54 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 9-133652975-A-G is Benign according to our data. Variant chr9-133652975-A-G is described in ClinVar as Benign. ClinVar VariationId is 365661.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.549 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.88 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.1410A>G	p.Thr470Thr	synonymous	Exon 9 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.1410A>G	p.Thr470Thr	synonymous	Exon 9 of 12	ENSP00000376776.2	P09172
	DBH	ENST00000860939.1		c.1410A>G	p.Thr470Thr	synonymous	Exon 9 of 12	ENSP00000530998.1

Frequencies

GnomAD3 genomes AF: 0.548 AC: 83153 AN: 151840 Hom.: 23203 Cov.: 32

Gnomad AFR AF: 0.570

Gnomad AMI AF: 0.696

Gnomad AMR AF: 0.609

Gnomad ASJ AF: 0.470

Gnomad EAS AF: 0.902

Gnomad SAS AF: 0.535

Gnomad FIN AF: 0.485

Gnomad MID AF: 0.579

Gnomad NFE AF: 0.507

Gnomad OTH AF: 0.515

GnomAD2 exomes AF: 0.566 AC: 142130 AN: 251046 AF XY: 0.557

Gnomad AFR exome AF: 0.582

Gnomad AMR exome AF: 0.695

Gnomad ASJ exome AF: 0.473

Gnomad EAS exome AF: 0.918

Gnomad FIN exome AF: 0.489

Gnomad NFE exome AF: 0.500

Gnomad OTH exome AF: 0.534

GnomAD4 exome AF: 0.525 AC: 766830 AN: 1460244 Hom.: 206126 Cov.: 40 AF XY: 0.525 AC XY: 381425 AN XY: 726482

African (AFR) AF: 0.576 AC: 19278 AN: 33464

American (AMR) AF: 0.686 AC: 30655 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.471 AC: 12307 AN: 26128

East Asian (EAS) AF: 0.905 AC: 35906 AN: 39694

South Asian (SAS) AF: 0.536 AC: 46190 AN: 86228

European-Finnish (FIN) AF: 0.482 AC: 25650 AN: 53168

Middle Eastern (MID) AF: 0.550 AC: 3164 AN: 5750

European-Non Finnish (NFE) AF: 0.506 AC: 561731 AN: 1110754

Other (OTH) AF: 0.529 AC: 31949 AN: 60352

GnomAD4 genome AF: 0.548 AC: 83206 AN: 151958 Hom.: 23211 Cov.: 32 AF XY: 0.549 AC XY: 40738 AN XY: 74264

African (AFR) AF: 0.570 AC: 23614 AN: 41440

American (AMR) AF: 0.609 AC: 9316 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.470 AC: 1629 AN: 3466

East Asian (EAS) AF: 0.902 AC: 4628 AN: 5130

South Asian (SAS) AF: 0.535 AC: 2583 AN: 4826

European-Finnish (FIN) AF: 0.485 AC: 5124 AN: 10562

Middle Eastern (MID) AF: 0.575 AC: 169 AN: 294

European-Non Finnish (NFE) AF: 0.507 AC: 34426 AN: 67924

Other (OTH) AF: 0.512 AC: 1082 AN: 2114

Alfa AF: 0.523 Hom.: 72621

Bravo AF: 0.563

Asia WGS AF: 0.673 AC: 2339 AN: 3478

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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	0.13
DANN	Benign	0.63
PhyloP100		-0.55
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: rs77905; hg19: chr9-136518097; COSMIC: COSV67548755; COSMIC: COSV67548755;