9-133636476-C-T

Position:

• chr9-133636476-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000787.4(DBH):​c.105C>T​(p.Ala35=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000677 in 1,613,070 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00042 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00070 (10 hom.)
• Consequence: DBH NM_000787.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.840

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant 9-133636476-C-T is Benign according to our data. Variant chr9-133636476-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 365630.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.84 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00042 (64/152306) while in subpopulation SAS AF= 0.00477 (23/4826). AF 95% confidence interval is 0.00326. There are 0 homozygotes in gnomad4. There are 39 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DBH	NM_000787.4	c.105C>T	p.Ala35=	synonymous_variant	1/12	ENST00000393056.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DBH	ENST00000393056.8	c.105C>T	p.Ala35=	synonymous_variant	1/12	1	NM_000787.4	P1
DBH	ENST00000263611.3	c.99C>T	p.Ala33=	synonymous_variant	1/3	2

Frequencies

GnomAD3 genomes AF: 0.000427 AC: 65 AN: 152188 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00497

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000397

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.00112 AC: 280 AN: 250320 Hom.: 3 AF XY: 0.00140 AC XY: 190 AN XY: 135524

Gnomad AFR exome AF: 0.0000619

Gnomad AMR exome AF: 0.000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00630

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000540

Gnomad OTH exome AF: 0.000818

GnomAD4 exome AF: 0.000704 AC: 1028 AN: 1460764 Hom.: 10 Cov.: 33 AF XY: 0.000895 AC XY: 650 AN XY: 726648

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.000582

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00611

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000351

Gnomad4 OTH exome AF: 0.000795

GnomAD4 genome AF: 0.000420 AC: 64 AN: 152306 Hom.: 0 Cov.: 32 AF XY: 0.000524 AC XY: 39 AN XY: 74486

Gnomad4 AFR AF: 0.0000962

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00477

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000397

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.000442 Hom.: 0

Bravo AF: 0.000389

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.000872

EpiControl AF: 0.000533

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Orthostatic hypotension 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 20, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	7.9
DANN	Benign	0.84

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: rs140025171; hg19: chr9-136501598; COSMIC: COSV104556987; COSMIC: COSV104556987;