9-133643810-G-C

Position:

• chr9-133643810-G-C

Variant summary

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

The NM_000787.4(DBH):​c.921+221G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.497 in 152,088 control chromosomes in the GnomAD database, including 19,439 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 0.50 (19439 hom., cov: 32)
• Consequence: DBH NM_000787.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.55

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=-1.02).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.553 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DBH	NM_000787.4	c.921+221G>C		intron_variant		ENST00000393056.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DBH	ENST00000393056.8	c.921+221G>C		intron_variant		1	NM_000787.4	P1

Frequencies

GnomAD3 genomes AF: 0.497 AC: 75476 AN: 151970 Hom.: 19412 Cov.: 32

Gnomad AFR AF: 0.559

Gnomad AMI AF: 0.328

Gnomad AMR AF: 0.379

Gnomad ASJ AF: 0.438

Gnomad EAS AF: 0.143

Gnomad SAS AF: 0.301

Gnomad FIN AF: 0.483

Gnomad MID AF: 0.436

Gnomad NFE AF: 0.534

Gnomad OTH AF: 0.477

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

GnomAD4 genome AF: 0.497 AC: 75562 AN: 152088 Hom.: 19439 Cov.: 32 AF XY: 0.486 AC XY: 36148 AN XY: 74340

Gnomad4 AFR AF: 0.559

Gnomad4 AMR AF: 0.379

Gnomad4 ASJ AF: 0.438

Gnomad4 EAS AF: 0.143

Gnomad4 SAS AF: 0.302

Gnomad4 FIN AF: 0.483

Gnomad4 NFE AF: 0.534

Gnomad4 OTH AF: 0.480

Alfa AF: 0.376 Hom.: 961

Bravo AF: 0.491

Asia WGS AF: 0.262 AC: 910 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.045
DANN	Benign	0.77

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: rs1611122; hg19: chr9-136508932;