rs41316996

Positions:

• chr9-133656532-G-A

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

The NM_000787.4(DBH):​c.1444G>A​(p.Gly482Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00255 in 1,613,898 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0018 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0026 (9 hom.)
• Consequence: DBH NM_000787.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 3.29

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-AS1 (HGNC:24155): (DBH antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -11 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.22667518).
• BP6: Variant 9-133656532-G-A is Benign according to our data. Variant chr9-133656532-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 529773.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=2}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00177 (269/152290) while in subpopulation NFE AF= 0.00338 (230/68018). AF 95% confidence interval is 0.00302. There are 0 homozygotes in gnomad4. There are 111 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DBH	NM_000787.4	c.1444G>A	p.Gly482Arg	missense_variant	10/12	ENST00000393056.8
DBH-AS1	NR_102735.1	n.288C>T		non_coding_transcript_exon_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DBH	ENST00000393056.8	c.1444G>A	p.Gly482Arg	missense_variant	10/12	1	NM_000787.4	P1
DBH-AS1	ENST00000425189.1	n.193C>T		non_coding_transcript_exon_variant	2/2	1

Frequencies

GnomAD3 genomes AF: 0.00177 AC: 269 AN: 152172 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000627

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00338

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00155 AC: 388 AN: 250774 Hom.: 0 AF XY: 0.00152 AC XY: 206 AN XY: 135714

Gnomad AFR exome AF: 0.000493

Gnomad AMR exome AF: 0.000318

Gnomad ASJ exome AF: 0.0000994

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000392

Gnomad FIN exome AF: 0.000465

Gnomad NFE exome AF: 0.00301

Gnomad OTH exome AF: 0.000817

GnomAD4 exome AF: 0.00263 AC: 3842 AN: 1461608 Hom.: 9 Cov.: 31 AF XY: 0.00256 AC XY: 1858 AN XY: 727100

Gnomad4 AFR exome AF: 0.000448

Gnomad4 AMR exome AF: 0.000224

Gnomad4 ASJ exome AF: 0.0000765

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000406

Gnomad4 FIN exome AF: 0.000376

Gnomad4 NFE exome AF: 0.00325

Gnomad4 OTH exome AF: 0.00220

GnomAD4 genome AF: 0.00177 AC: 269 AN: 152290 Hom.: 0 Cov.: 33 AF XY: 0.00149 AC XY: 111 AN XY: 74468

Gnomad4 AFR AF: 0.000626

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.00338

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00274 Hom.: 2

Bravo AF: 0.00179

TwinsUK AF: 0.00351 AC: 13

ALSPAC AF: 0.00337 AC: 13

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00279 AC: 24

ExAC AF: 0.00169 AC: 205

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Orthostatic hypotension 1 Uncertain:1 Benign:1

Uncertain significance, 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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Dec 09, 2023	- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Sep 02, 2022

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 25450229, 22028891) -

DBH-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 14, 2022

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

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Benign	-0.079	T
BayesDel_noAF	Uncertain	0.11
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.76	D
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.23	T
MetaSVM	Uncertain	-0.0046	T
MutationAssessor	Pathogenic	3.3	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-4.2	D
REVEL	Pathogenic	0.69
Sift	Uncertain	0.0040	D
Sift4G	Benign	0.12	T
Polyphen		0.94	P
Vest4		0.86
MutPred		0.68		Loss of glycosylation at T477 (P = 0.1173);
MVP		0.82
MPC		0.39
ClinPred		0.072	T
GERP RS		3.5
Varity_R		0.70
gMVP		0.92

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs41316996; hg19: chr9-136521654;