rs3025380

chr9-133636634-G-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP3 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000787.4(DBH):c.263G>C(p.Gly88Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00398 in 1,613,152 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0034 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0040 (28 hom.)
• Consequence: DBH NM_000787.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 9.44

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 -19 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 9: AlphaMissense, BayesDel_noAF, Cadd, Eigen, M_CAP, MutationAssessor, phyloP100way_vertebrate, PROVEAN, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.025107235).
• BP6: Variant 9-133636634-G-C is Benign according to our data. Variant chr9-133636634-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 365634.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00338 (514/152270) while in subpopulation NFE AF= 0.00503 (342/68014). AF 95% confidence interval is 0.00459. There are 1 homozygotes in gnomad4. There are 225 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DBH	NM_000787.4	c.263G>C	p.Gly88Ala	missense_variant	1/12	ENST00000393056.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DBH	ENST00000393056.8	c.263G>C	p.Gly88Ala	missense_variant	1/12	1	NM_000787.4	P1
DBH	ENST00000263611.3	c.257G>C	p.Gly86Ala	missense_variant	1/3	2

Frequencies

GnomAD3 genomes AF: 0.00338 AC: 514 AN: 152152 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000845

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00406

Gnomad ASJ AF: 0.0124

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00160

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00503

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00342 AC: 849 AN: 248262 Hom.: 3 AF XY: 0.00334 AC XY: 449 AN XY: 134512

Gnomad AFR exome AF: 0.000924

Gnomad AMR exome AF: 0.00220

Gnomad ASJ exome AF: 0.0148

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00154

Gnomad FIN exome AF: 0.00182

Gnomad NFE exome AF: 0.00443

Gnomad OTH exome AF: 0.00507

GnomAD4 exome AF: 0.00405 AC: 5912 AN: 1460882 Hom.: 28 Cov.: 33 AF XY: 0.00395 AC XY: 2873 AN XY: 726804

Gnomad4 AFR exome AF: 0.00105

Gnomad4 AMR exome AF: 0.00239

Gnomad4 ASJ exome AF: 0.0152

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00157

Gnomad4 FIN exome AF: 0.00139

Gnomad4 NFE exome AF: 0.00433

Gnomad4 OTH exome AF: 0.00497

GnomAD4 genome AF: 0.00338 AC: 514 AN: 152270 Hom.: 1 Cov.: 32 AF XY: 0.00302 AC XY: 225 AN XY: 74482

Gnomad4 AFR AF: 0.000866

Gnomad4 AMR AF: 0.00405

Gnomad4 ASJ AF: 0.0124

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.00160

Gnomad4 NFE AF: 0.00503

Gnomad4 OTH AF: 0.00332

Alfa AF: 0.00460 Hom.: 4

Bravo AF: 0.00351

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00415 AC: 16

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00384 AC: 33

ExAC AF: 0.00350 AC: 425

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00382

EpiControl AF: 0.00456

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Orthostatic hypotension 1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

DBH-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 24, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Nov 01, 2023

DBH: BS1 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Pathogenic	0.45
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D;.
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Pathogenic	0.35	D
MetaRNN	Benign	0.025	T;T
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.2	M;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.60	T
PROVEAN	Pathogenic	-4.8	D;.
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;.
Polyphen		1.0	D;.
Vest4		0.97
MVP		0.88
MPC		0.38
ClinPred		0.025	T
GERP RS		5.2
Varity_R		0.91
gMVP		0.96

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: rs3025380; hg19: chr9-136501756; COSMIC: COSV55041047; COSMIC: COSV55041047;