Genetic Variant NM_000787.4:c.339+109G>C (chr9-133636819-G-C) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000787.4(DBH):c.339+109G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.3 in 1,042,436 control chromosomes in the GnomAD database, including 51,882 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.31 ( 7746 hom., cov: 32)

Exomes 𝑓: 0.30 ( 44136 hom. )

Consequence

DBH
NM_000787.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.0930

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.91).

BP6

Variant 9-133636819-G-C is Benign according to our data. Variant chr9-133636819-G-C is described in ClinVar as [Benign]. Clinvar id is 1282926.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.34 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DBH	NM_000787.4 link	c.339+109G>C		intron_variant	Intron 1 of 11	ENST00000393056.8	NP_000778.3	P09172

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DBH	ENST00000393056.8 link	c.339+109G>C		intron_variant	Intron 1 of 11	1	NM_000787.4	ENSP00000376776.2		P09172
DBH	ENST00000263611.3 link	c.333+109G>C		intron_variant	Intron 1 of 2	2		ENSP00000263611.3		Q5T382

Frequencies

GnomAD3 genomes

AF:

0.310

AC:

47110

AN:

151796

Hom.:

7738

Cov.:

show subpopulations

Gnomad AFR

AF:

0.340

Gnomad AMI

AF:

0.241

Gnomad AMR

AF:

0.246

Gnomad ASJ

AF:

0.248

Gnomad EAS

AF:

0.00232

Gnomad SAS

AF:

0.132

Gnomad FIN

AF:

0.334

Gnomad MID

AF:

0.301

Gnomad NFE

AF:

0.344

Gnomad OTH

AF:

0.294

GnomAD4 exome

AF:

0.299

AC:

265836

AN:

890522

Hom.:

44136

AF XY:

0.294

AC XY:

134579

AN XY:

458442

show subpopulations

Gnomad4 AFR exome

AF:

0.331

Gnomad4 AMR exome

AF:

0.193

Gnomad4 ASJ exome

AF:

0.247

Gnomad4 EAS exome

AF:

0.00160

Gnomad4 SAS exome

AF:

0.141

Gnomad4 FIN exome

AF:

0.342

Gnomad4 NFE exome

AF:

0.338

Gnomad4 OTH exome

AF:

0.280

GnomAD4 genome

AF:

0.310

AC:

47146

AN:

151914

Hom.:

7746

Cov.:

AF XY:

0.304

AC XY:

22541

AN XY:

74254

show subpopulations

Gnomad4 AFR

AF:

0.340

Gnomad4 AMR

AF:

0.246

Gnomad4 ASJ

AF:

0.248

Gnomad4 EAS

AF:

0.00232

Gnomad4 SAS

AF:

0.131

Gnomad4 FIN

AF:

0.334

Gnomad4 NFE

AF:

0.344

Gnomad4 OTH

AF:

0.290

Alfa

AF:

0.196

Hom.:

433

Bravo

AF:

0.304

Asia WGS

AF:

0.0830

AC:

290

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 11, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

2.4

DANN

Benign

0.49

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over