9-133636517-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_000787.4(DBH):c.146A>G(p.Tyr49Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000013 in 1,461,152 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y49F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000013 (1 hom.)
• Consequence: DBH NM_000787.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.36

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.765

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DBH	NM_000787.4	c.146A>G	p.Tyr49Cys	missense_variant	1/12	ENST00000393056.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DBH	ENST00000393056.8	c.146A>G	p.Tyr49Cys	missense_variant	1/12	1	NM_000787.4	P1
DBH	ENST00000263611.3	c.140A>G	p.Tyr47Cys	missense_variant	1/3	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000240 AC: 6 AN: 249856 Hom.: 0 AF XY: 0.0000443 AC XY: 6 AN XY: 135350

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000130 AC: 19 AN: 1461152 Hom.: 1 Cov.: 33 AF XY: 0.0000234 AC XY: 17 AN XY: 726922

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000209

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Orthostatic hypotension 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 07, 2023

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 49 of the DBH protein (p.Tyr49Cys). This variant is present in population databases (rs745685569, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with DBH-related conditions. ClinVar contains an entry for this variant (Variation ID: 565924). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt DBH protein function. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.13
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.83	D;.
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.83	T;T
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.77	D;D
MetaSVM	Benign	-0.65	T
MutationAssessor	Uncertain	2.7	M;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-6.1	D;.
REVEL	Uncertain	0.30
Sift	Uncertain	0.0070	D;.
Sift4G	Uncertain	0.0090	D;.
Polyphen		0.99	D;.
Vest4		0.65
MutPred		0.64		Gain of catalytic residue at P48 (P = 0.0102);.;
MVP		0.69
MPC		0.39
ClinPred		0.79	D
GERP RS		3.1
Varity_R		0.50
gMVP		0.92

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: rs745685569; hg19: chr9-136501639; COSMIC: COSV55041752; COSMIC: COSV55041752;