9-133656438-T-C

Variant names:

• chr9-133656438-T-C
• rs60202024
• NM_000787.4:c.1435-85T>C

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.1435-85T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00479 in 1,584,744 control chromosomes in the GnomAD database, including 305 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.024 (155 hom., cov: 33)
  • Exomes 𝑓: 0.0027 (150 hom.)
• Consequence: DBH NM_000787.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.26
• Publications: 0 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-AS1 (HGNC:24155): (DBH antisense RNA 1)

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 9-133656438-T-C is Benign according to our data. Variant chr9-133656438-T-C is described in ClinVar as Benign. ClinVar VariationId is 1232562.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0801 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.1435-85T>C		intron	N/A	NP_000778.3
	DBH-AS1	NR_102735.1		n.382A>G		non_coding_transcript_exon	Exon 2 of 2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DBH	ENST00000393056.8	TSL:1 MANE Select	c.1435-85T>C		intron	N/A	ENSP00000376776.2	P09172
	DBH-AS1	ENST00000425189.1	TSL:1	n.287A>G		non_coding_transcript_exon	Exon 2 of 2
	DBH	ENST00000860939.1		c.1435-85T>C		intron	N/A	ENSP00000530998.1

Frequencies

GnomAD3 genomes AF: 0.0239 AC: 3637 AN: 152124 Hom.: 155 Cov.: 33

Gnomad AFR AF: 0.0823

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00975

Gnomad ASJ AF: 0.00432

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000382

Gnomad OTH AF: 0.0182

GnomAD4 exome AF: 0.00275 AC: 3937 AN: 1432502 Hom.: 150 Cov.: 26 AF XY: 0.00252 AC XY: 1800 AN XY: 714002

African (AFR) AF: 0.0882 AC: 2899 AN: 32858

American (AMR) AF: 0.00526 AC: 234 AN: 44506

Ashkenazi Jewish (ASJ) AF: 0.00244 AC: 63 AN: 25868

East Asian (EAS) AF: 0.00 AC: 0 AN: 39438

South Asian (SAS) AF: 0.000235 AC: 20 AN: 85048

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50094

Middle Eastern (MID) AF: 0.00715 AC: 41 AN: 5736

European-Non Finnish (NFE) AF: 0.000268 AC: 292 AN: 1089560

Other (OTH) AF: 0.00653 AC: 388 AN: 59394

GnomAD4 genome AF: 0.0240 AC: 3650 AN: 152242 Hom.: 155 Cov.: 33 AF XY: 0.0223 AC XY: 1661 AN XY: 74448

African (AFR) AF: 0.0824 AC: 3418 AN: 41500

American (AMR) AF: 0.00974 AC: 149 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00432 AC: 15 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000382 AC: 26 AN: 68018

Other (OTH) AF: 0.0180 AC: 38 AN: 2112

Alfa AF: 0.0123 Hom.: 27

Bravo AF: 0.0272

Asia WGS AF: 0.00635 AC: 22 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.33
DANN	Benign	0.48
PhyloP100		-1.3
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs60202024; hg19: chr9-136521560;