rs5324

chr9-133643536-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000787.4(DBH):c.868G>A(p.Asp290Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00406 in 1,613,278 control chromosomes in the GnomAD database, including 176 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.020 (84 hom., cov: 32)
  • Exomes 𝑓: 0.0024 (92 hom.)
• Consequence: DBH NM_000787.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.270

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00285092).
• BP6: Variant 9-133643536-G-A is Benign according to our data. Variant chr9-133643536-G-A is described in ClinVar as [Benign]. Clinvar id is 365650.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0646 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DBH	NM_000787.4	c.868G>A	p.Asp290Asn	missense_variant	4/12	ENST00000393056.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DBH	ENST00000393056.8	c.868G>A	p.Asp290Asn	missense_variant	4/12	1	NM_000787.4	P1
DBH	ENST00000263611.3	c.715G>A	p.Asp239Asn	missense_variant	3/3	2

Frequencies

GnomAD3 genomes AF: 0.0197 AC: 2987 AN: 151680 Hom.: 82 Cov.: 32

Gnomad AFR AF: 0.0664

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00907

Gnomad ASJ AF: 0.00548

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000417

Gnomad FIN AF: 0.0000948

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000633

Gnomad OTH AF: 0.0187

GnomAD3 exomes AF: 0.00577 AC: 1446 AN: 250800 Hom.: 41 AF XY: 0.00426 AC XY: 579 AN XY: 135770

Gnomad AFR exome AF: 0.0705

Gnomad AMR exome AF: 0.00486

Gnomad ASJ exome AF: 0.00408

Gnomad EAS exome AF: 0.0000545

Gnomad SAS exome AF: 0.000261

Gnomad FIN exome AF: 0.000324

Gnomad NFE exome AF: 0.000547

Gnomad OTH exome AF: 0.00326

GnomAD4 exome AF: 0.00243 AC: 3547 AN: 1461480 Hom.: 92 Cov.: 34 AF XY: 0.00217 AC XY: 1576 AN XY: 727052

Gnomad4 AFR exome AF: 0.0707

Gnomad4 AMR exome AF: 0.00523

Gnomad4 ASJ exome AF: 0.00417

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000290

Gnomad4 FIN exome AF: 0.000188

Gnomad4 NFE exome AF: 0.000411

Gnomad4 OTH exome AF: 0.00507

GnomAD4 genome AF: 0.0198 AC: 3003 AN: 151798 Hom.: 84 Cov.: 32 AF XY: 0.0192 AC XY: 1423 AN XY: 74154

Gnomad4 AFR AF: 0.0666

Gnomad4 AMR AF: 0.00899

Gnomad4 ASJ AF: 0.00548

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000417

Gnomad4 FIN AF: 0.0000948

Gnomad4 NFE AF: 0.000633

Gnomad4 OTH AF: 0.0185

Alfa AF: 0.00425 Hom.: 31

Bravo AF: 0.0223

ESP6500AA AF: 0.0681 AC: 300

ESP6500EA AF: 0.00116 AC: 10

ExAC AF: 0.00668 AC: 811

Asia WGS AF: 0.00606 AC: 22 AN: 3478

EpiCase AF: 0.00158

EpiControl AF: 0.000771

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Orthostatic hypotension 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 04, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.65
Cadd	Benign	7.3
Dann	Uncertain	0.99
DEOGEN2	Benign	0.12	T;.
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.052	N
LIST_S2	Benign	0.74	T;T
MetaRNN	Benign	0.0029	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.2	M;.
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.0	N;.
REVEL	Benign	0.063
Sift	Benign	0.23	T;.
Sift4G	Benign	0.42	T;.
Polyphen		0.24	B;.
Vest4		0.12
MVP		0.19
MPC		0.057
ClinPred		0.011	T
GERP RS		0.65
Varity_R		0.24
gMVP		0.50

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

Publications

LitVar

Other links and lift over

dbSNP: rs5324; hg19: chr9-136508658; COSMIC: COSV55040628;