rs41316996

Variant names:

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_ModerateBP6BS1BS2

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

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:2

Conservation

PhyloP100: 3.29

Publications

8 publications found

Variant links:

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 links:

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

DBH-AS1 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_000787.4, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 529773.

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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 9 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000787.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DBH	NM_000787.4	MANE Select	c.1444G>A	p.Gly482Arg	missense	Exon 10 of 12	NP_000778.3
	DBH-AS1	NR_102735.1		n.288C>T		non_coding_transcript_exon	Exon 2 of 2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DBH	ENST00000393056.8	TSL:1 MANE Select	c.1444G>A	p.Gly482Arg	missense	Exon 10 of 12	ENSP00000376776.2	P09172
DBH-AS1	ENST00000425189.1	TSL:1	n.193C>T		non_coding_transcript_exon	Exon 2 of 2
DBH	ENST00000860939.1		c.1444G>A	p.Gly482Arg	missense	Exon 10 of 12	ENSP00000530998.1

Frequencies

GnomAD3 genomes

AF:

0.00177

AC:

269

AN:

152172

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.00155

AC:

388

AN:

250774

AF XY:

0.00152

show subpopulations

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 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.:

Cov.:

AF XY:

0.00256

AC XY:

1858

AN XY:

727100

show subpopulations

African (AFR)

AF:

0.000448

AC:

AN:

33480

American (AMR)

AF:

0.000224

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.0000765

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.000406

AC:

AN:

86240

European-Finnish (FIN)

AF:

0.000376

AC:

AN:

53188

Middle Eastern (MID)

AF:

0.00156

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00325

AC:

3618

AN:

1111988

Other (OTH)

AF:

0.00220

AC:

133

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

232

463

695

926

1158

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

134

268

402

536

670

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00177

AC:

269

AN:

152290

Hom.:

Cov.:

AF XY:

0.00149

AC XY:

111

AN XY:

74468

show subpopulations

African (AFR)

AF:

0.000626

AC:

AN:

41564

American (AMR)

AF:

0.000327

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.000415

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.000377

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00338

AC:

230

AN:

68018

Other (OTH)

AF:

0.00

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00259

Hom.:

Bravo

AF:

0.00179

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Orthostatic hypotension 1 (2)

DBH-related disorder (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.40

BayesDel_addAF

Benign

-0.079

BayesDel_noAF

Uncertain

0.11

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.76

Eigen

Uncertain

0.36

Eigen_PC

Uncertain

0.28

FATHMM_MKL

Uncertain

0.79

LIST_S2

Uncertain

0.94

M_CAP

Uncertain

0.15

MetaRNN

Benign

0.23

MetaSVM

Uncertain

-0.0046

MutationAssessor

Pathogenic

3.3

PhyloP100

3.3

PrimateAI

Uncertain

0.54

PROVEAN

Uncertain

-4.2

REVEL

Pathogenic

0.69

Sift

Uncertain

0.0040

Sift4G

Benign

0.12

Varity_R

0.70

gMVP

0.92

Mutation Taster

=37/63

disease causing

(source)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over