rs76856960

Variant names:

• chr9-133636447-G-A
• rs76856960
• NM_000787.4:c.76G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000787.4(DBH):​c.76G>A​(p.Val26Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0042 in 1,612,912 control chromosomes in the GnomAD database, including 41 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0038 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0042 (38 hom.)
• Consequence: DBH NM_000787.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.20
• Publications: 12 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: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008224636).
• BP6: Variant 9-133636447-G-A is Benign according to our data. Variant chr9-133636447-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 779694.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00377 (575/152328) while in subpopulation SAS AF = 0.0135 (65/4830). AF 95% confidence interval is 0.0108. There are 3 homozygotes in GnomAd4. There are 298 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

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.76G>A	p.Val26Met	missense	Exon 1 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.76G>A	p.Val26Met	missense	Exon 1 of 12	ENSP00000376776.2	P09172
	DBH	ENST00000860939.1		c.76G>A	p.Val26Met	missense	Exon 1 of 12	ENSP00000530998.1
	DBH	ENST00000263611.3	TSL:2	c.70G>A	p.Val24Met	missense	Exon 1 of 3	ENSP00000263611.3	Q5T382

Frequencies

GnomAD3 genomes AF: 0.00378 AC: 575 AN: 152210 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000651

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0134

Gnomad FIN AF: 0.00772

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.00554

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00512 AC: 1283 AN: 250370 AF XY: 0.00583

Gnomad AFR exome AF: 0.000742

Gnomad AMR exome AF: 0.00133

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00789

Gnomad NFE exome AF: 0.00569

Gnomad OTH exome AF: 0.00490

GnomAD4 exome AF: 0.00425 AC: 6205 AN: 1460584 Hom.: 38 Cov.: 33 AF XY: 0.00466 AC XY: 3383 AN XY: 726564

African (AFR) AF: 0.000687 AC: 23 AN: 33478

American (AMR) AF: 0.00130 AC: 58 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.000191 AC: 5 AN: 26132

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39682

South Asian (SAS) AF: 0.0121 AC: 1045 AN: 86248

European-Finnish (FIN) AF: 0.00809 AC: 424 AN: 52400

Middle Eastern (MID) AF: 0.00867 AC: 50 AN: 5768

European-Non Finnish (NFE) AF: 0.00392 AC: 4356 AN: 1111790

Other (OTH) AF: 0.00402 AC: 243 AN: 60374

GnomAD4 genome AF: 0.00377 AC: 575 AN: 152328 Hom.: 3 Cov.: 32 AF XY: 0.00400 AC XY: 298 AN XY: 74498

African (AFR) AF: 0.000649 AC: 27 AN: 41580

American (AMR) AF: 0.00111 AC: 17 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.0135 AC: 65 AN: 4830

European-Finnish (FIN) AF: 0.00772 AC: 82 AN: 10624

Middle Eastern (MID) AF: 0.00685 AC: 2 AN: 292

European-Non Finnish (NFE) AF: 0.00554 AC: 377 AN: 68020

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.00469 Hom.: 9

Bravo AF: 0.00249

TwinsUK AF: 0.00297 AC: 11

ALSPAC AF: 0.00337 AC: 13

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00453 AC: 39

ExAC AF: 0.00577 AC: 700

Asia WGS AF: 0.00606 AC: 22 AN: 3478

EpiCase AF: 0.00513

EpiControl AF: 0.00522

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.36
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.26	T
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Benign	0.73	D
LIST_S2	Uncertain	0.90	D
MetaRNN	Benign	0.0082	T
MetaSVM	Benign	-0.81	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		1.2
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.67	N
REVEL	Benign	0.14
Sift	Benign	0.047	D
Sift4G	Benign	0.12	T
Polyphen		0.93	P
Vest4		0.43
MVP		0.59
MPC		0.25
ClinPred		0.025	T
GERP RS		4.6
PromoterAI		0.036	Neutral
Varity_R		0.053
gMVP		0.50
Mutation Taster		=96/4	polymorphism

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: rs76856960; hg19: chr9-136501569; COSMIC: COSV55040586; COSMIC: COSV55040586;