9-133647393-T-C

Position:

• chr9-133647393-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000787.4(DBH):​c.1025-453T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.769 in 152,138 control chromosomes in the GnomAD database, including 46,200 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 0.77 (46200 hom., cov: 32)
• Consequence: DBH NM_000787.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.603

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.975 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DBH	NM_000787.4	c.1025-453T>C		intron_variant		ENST00000393056.8	NP_000778.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DBH	ENST00000393056.8	c.1025-453T>C		intron_variant		1	NM_000787.4	ENSP00000376776.2

Frequencies

GnomAD3 genomes AF: 0.769 AC: 116923 AN: 152020 Hom.: 46137 Cov.: 32

Gnomad AFR AF: 0.930

Gnomad AMI AF: 0.789

Gnomad AMR AF: 0.800

Gnomad ASJ AF: 0.705

Gnomad EAS AF: 0.997

Gnomad SAS AF: 0.845

Gnomad FIN AF: 0.690

Gnomad MID AF: 0.731

Gnomad NFE AF: 0.657

Gnomad OTH AF: 0.760

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

GnomAD4 genome AF: 0.769 AC: 117047 AN: 152138 Hom.: 46200 Cov.: 32 AF XY: 0.772 AC XY: 57433 AN XY: 74352

Gnomad4 AFR AF: 0.931

Gnomad4 AMR AF: 0.800

Gnomad4 ASJ AF: 0.705

Gnomad4 EAS AF: 0.997

Gnomad4 SAS AF: 0.844

Gnomad4 FIN AF: 0.690

Gnomad4 NFE AF: 0.657

Gnomad4 OTH AF: 0.764

Alfa AF: 0.701 Hom.: 19252

Bravo AF: 0.786

Asia WGS AF: 0.928 AC: 3229 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	6.8
DANN	Benign	0.71

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: rs2797853; hg19: chr9-136512515;