9-133636447-G-A

Variant summary

Our verdict is Benign. Variant got -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 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 criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.20

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=0.008224636).
• BP6: Variant 9-133636447-G-A is Benign according to our data. Variant chr9-133636447-G-A is described in ClinVar as [Benign]. Clinvar id 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DBH	NM_000787.4	c.76G>A	p.Val26Met	missense_variant	1/12	ENST00000393056.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DBH	ENST00000393056.8	c.76G>A	p.Val26Met	missense_variant	1/12	1	NM_000787.4	P1
DBH	ENST00000263611.3	c.70G>A	p.Val24Met	missense_variant	1/3	2

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

GnomAD3 exomes AF: 0.00512 AC: 1283 AN: 250370 Hom.: 9 AF XY: 0.00583 AC XY: 791 AN XY: 135590

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 SAS exome AF: 0.0125

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

Gnomad4 AFR exome AF: 0.000687

Gnomad4 AMR exome AF: 0.00130

Gnomad4 ASJ exome AF: 0.000191

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0121

Gnomad4 FIN exome AF: 0.00809

Gnomad4 NFE exome AF: 0.00392

Gnomad4 OTH exome AF: 0.00402

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

Gnomad4 AFR AF: 0.000649

Gnomad4 AMR AF: 0.00111

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0135

Gnomad4 FIN AF: 0.00772

Gnomad4 NFE AF: 0.00554

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00485 Hom.: 3

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

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	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jan 01, 2024

DBH: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

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;D
MetaRNN	Benign	0.0082	T;T
MetaSVM	Benign	-0.81	T
MutationAssessor	Uncertain	2.7	M;.
MutationTaster	Benign	0.98	D
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
Varity_R		0.053
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: rs76856960; hg19: chr9-136501569; COSMIC: COSV55040586; COSMIC: COSV55040586;