9-133647153-T-C

Variant names:

• chr9-133647153-T-C
• rs2519154
• NM_000787.4:c.1025-693T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000787.4(DBH):​c.1025-693T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.439 in 152,034 control chromosomes in the GnomAD database, including 16,005 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 0.44 (16005 hom., cov: 32)
• Consequence: DBH NM_000787.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.24
• Publications: 19 publications found

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 Gene-Disease associations (from GenCC):

• orthostatic hypotension 1

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet

ACMG classification

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 = 0.891 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DBH	NM_000787.4	MANE Select	c.1025-693T>C		intron	N/A	NP_000778.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DBH	ENST00000393056.8	TSL:1 MANE Select	c.1025-693T>C		intron	N/A	ENSP00000376776.2

Frequencies

GnomAD3 genomes AF: 0.440 AC: 66779 AN: 151916 Hom.: 16014 Cov.: 32

Gnomad AFR AF: 0.301

Gnomad AMI AF: 0.646

Gnomad AMR AF: 0.599

Gnomad ASJ AF: 0.439

Gnomad EAS AF: 0.913

Gnomad SAS AF: 0.654

Gnomad FIN AF: 0.506

Gnomad MID AF: 0.478

Gnomad NFE AF: 0.423

Gnomad OTH AF: 0.457

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.439 AC: 66797 AN: 152034 Hom.: 16005 Cov.: 32 AF XY: 0.452 AC XY: 33621 AN XY: 74344

African (AFR) AF: 0.301 AC: 12490 AN: 41464

American (AMR) AF: 0.599 AC: 9162 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.439 AC: 1523 AN: 3468

East Asian (EAS) AF: 0.913 AC: 4713 AN: 5164

South Asian (SAS) AF: 0.653 AC: 3142 AN: 4814

European-Finnish (FIN) AF: 0.506 AC: 5356 AN: 10582

Middle Eastern (MID) AF: 0.469 AC: 138 AN: 294

European-Non Finnish (NFE) AF: 0.423 AC: 28718 AN: 67940

Other (OTH) AF: 0.458 AC: 968 AN: 2114

Alfa AF: 0.437 Hom.: 44233

Bravo AF: 0.443

Asia WGS AF: 0.731 AC: 2542 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	0.17
DANN	Benign	0.47
PhyloP100		-2.2
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2519154; hg19: chr9-136512275;