chr9-133644190-C-T

Variant names:

• chr9-133644190-C-T
• rs1611125
• NM_000787.4:c.922-28C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000787.4(DBH):​c.922-28C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.504 in 1,564,790 control chromosomes in the GnomAD database, including 206,417 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.51 (20354 hom., cov: 33)
  • Exomes 𝑓: 0.50 (186063 hom.)
• Consequence: DBH NM_000787.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.939
• Publications: 18 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: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BP6: Variant 9-133644190-C-T is Benign according to our data. Variant chr9-133644190-C-T is described in ClinVar as Benign. ClinVar VariationId is 1246402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.59 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.922-28C>T		intron	N/A	NP_000778.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DBH	ENST00000393056.8	TSL:1 MANE Select	c.922-28C>T		intron	N/A	ENSP00000376776.2	P09172
	DBH	ENST00000860939.1		c.922-28C>T		intron	N/A	ENSP00000530998.1

Frequencies

GnomAD3 genomes AF: 0.507 AC: 77092 AN: 151996 Hom.: 20317 Cov.: 33

Gnomad AFR AF: 0.596

Gnomad AMI AF: 0.329

Gnomad AMR AF: 0.384

Gnomad ASJ AF: 0.442

Gnomad EAS AF: 0.142

Gnomad SAS AF: 0.296

Gnomad FIN AF: 0.483

Gnomad MID AF: 0.443

Gnomad NFE AF: 0.534

Gnomad OTH AF: 0.485

GnomAD2 exomes AF: 0.438 AC: 109897 AN: 250822 AF XY: 0.439

Gnomad AFR exome AF: 0.595

Gnomad AMR exome AF: 0.278

Gnomad ASJ exome AF: 0.453

Gnomad EAS exome AF: 0.139

Gnomad FIN exome AF: 0.493

Gnomad NFE exome AF: 0.532

Gnomad OTH exome AF: 0.459

GnomAD4 exome AF: 0.503 AC: 710862 AN: 1412676 Hom.: 186063 Cov.: 25 AF XY: 0.497 AC XY: 351000 AN XY: 705888

African (AFR) AF: 0.602 AC: 19455 AN: 32298

American (AMR) AF: 0.290 AC: 12927 AN: 44644

Ashkenazi Jewish (ASJ) AF: 0.453 AC: 11696 AN: 25818

East Asian (EAS) AF: 0.147 AC: 5803 AN: 39508

South Asian (SAS) AF: 0.324 AC: 27646 AN: 85358

European-Finnish (FIN) AF: 0.501 AC: 26639 AN: 53210

Middle Eastern (MID) AF: 0.431 AC: 2433 AN: 5648

European-Non Finnish (NFE) AF: 0.540 AC: 576238 AN: 1067498

Other (OTH) AF: 0.477 AC: 28025 AN: 58694

GnomAD4 genome AF: 0.507 AC: 77191 AN: 152114 Hom.: 20354 Cov.: 33 AF XY: 0.497 AC XY: 36949 AN XY: 74368

African (AFR) AF: 0.596 AC: 24744 AN: 41494

American (AMR) AF: 0.384 AC: 5875 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.442 AC: 1533 AN: 3472

East Asian (EAS) AF: 0.142 AC: 736 AN: 5182

South Asian (SAS) AF: 0.297 AC: 1430 AN: 4822

European-Finnish (FIN) AF: 0.483 AC: 5110 AN: 10582

Middle Eastern (MID) AF: 0.455 AC: 133 AN: 292

European-Non Finnish (NFE) AF: 0.534 AC: 36302 AN: 67966

Other (OTH) AF: 0.488 AC: 1029 AN: 2110

Alfa AF: 0.521 Hom.: 8123

Bravo AF: 0.503

Asia WGS AF: 0.262 AC: 913 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Orthostatic hypotension 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.22
DANN	Benign	0.41
PhyloP100		-0.94
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1611125; hg19: chr9-136509312; COSMIC: COSV55041534; COSMIC: COSV55041534;