Genetic Variant DBH:c.1435-983T>C (chr9-133655540-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_000787.4(DBH):c.1435-983T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.422 in 152,196 control chromosomes in the GnomAD database, including 13,611 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.42 ( 13599 hom., cov: 33)

Exomes 𝑓: 0.44 ( 12 hom. )

Consequence

DBH
NM_000787.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -4.31

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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.92).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.51 is higher than 0.05.

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.1435-983T>C		intron	N/A	NP_000778.3
	DBH-AS1	NR_102735.1		n.1280A>G		non_coding_transcript_exon	Exon 2 of 2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
DBH	ENST00000393056.8	TSL:1 MANE Select	c.1435-983T>C	intron	N/A	ENSP00000376776.2
DBH-AS1	ENST00000425189.1	TSL:1	n.1185A>G	non_coding_transcript_exon	Exon 2 of 2
DBH	ENST00000860939.1		c.1435-983T>C	intron	N/A	ENSP00000530998.1

Frequencies

GnomAD3 genomes

AF:

0.422

AC:

64089

AN:

151976

Hom.:

13583

Cov.:

show subpopulations

Gnomad AFR

AF:

0.399

Gnomad AMI

AF:

0.610

Gnomad AMR

AF:

0.431

Gnomad ASJ

AF:

0.400

Gnomad EAS

AF:

0.526

Gnomad SAS

AF:

0.336

Gnomad FIN

AF:

0.430

Gnomad MID

AF:

0.402

Gnomad NFE

AF:

0.429

Gnomad OTH

AF:

0.402

GnomAD4 exome

AF:

0.441

AC:

AN:

102

Hom.:

Cov.:

AF XY:

0.443

AC XY:

AN XY:

show subpopulations

African (AFR)

AF:

0.500

AC:

AN:

American (AMR)

AF:

0.500

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AF:

1.00

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AF:

0.667

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.375

AC:

AN:

Other (OTH)

AF:

0.700

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.573

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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

GnomAD4 genome

AF:

0.422

AC:

64134

AN:

152094

Hom.:

13599

Cov.:

AF XY:

0.419

AC XY:

31157

AN XY:

74366

show subpopulations

African (AFR)

AF:

0.399

AC:

16564

AN:

41482

American (AMR)

AF:

0.431

AC:

6588

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.400

AC:

1388

AN:

3472

East Asian (EAS)

AF:

0.527

AC:

2719

AN:

5162

South Asian (SAS)

AF:

0.337

AC:

1626

AN:

4828

European-Finnish (FIN)

AF:

0.430

AC:

4545

AN:

10580

Middle Eastern (MID)

AF:

0.401

AC:

118

AN:

294

European-Non Finnish (NFE)

AF:

0.429

AC:

29187

AN:

67970

Other (OTH)

AF:

0.399

AC:

843

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

1981

3963

5944

7926

9907

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

600

1200

1800

2400

3000

<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:

0.422

Hom.:

5708

Bravo

AF:

0.425

Asia WGS

AF:

0.417

AC:

1451

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.92

CADD

Benign

0.73

(source)

DANN

Benign

0.45

PhyloP100

-4.3

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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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