rs41316996
Positions:
Variant summary
Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_ModerateBP6BS1BS2
The NM_000787.4(DBH):c.1444G>A(p.Gly482Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00255 in 1,613,898 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.0018 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0026 ( 9 hom. )
Consequence
DBH
NM_000787.4 missense
NM_000787.4 missense
Scores
2
13
4
Clinical Significance
Conservation
PhyloP100: 3.29
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]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -11 ACMG points.
BP4
?
Computational evidence support a benign effect (MetaRNN=0.22667518).
BP6
?
Variant 9-133656532-G-A is Benign according to our data. Variant chr9-133656532-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 529773.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=2}.
BS1
?
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00177 (269/152290) while in subpopulation NFE AF= 0.00338 (230/68018). AF 95% confidence interval is 0.00302. There are 0 homozygotes in gnomad4. There are 111 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
?
High Homozygotes in GnomAdExome4 at 9 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DBH | NM_000787.4 | c.1444G>A | p.Gly482Arg | missense_variant | 10/12 | ENST00000393056.8 | |
DBH-AS1 | NR_102735.1 | n.288C>T | non_coding_transcript_exon_variant | 2/2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DBH | ENST00000393056.8 | c.1444G>A | p.Gly482Arg | missense_variant | 10/12 | 1 | NM_000787.4 | P1 | |
DBH-AS1 | ENST00000425189.1 | n.193C>T | non_coding_transcript_exon_variant | 2/2 | 1 |
Frequencies
GnomAD3 genomes ? AF: 0.00177 AC: 269AN: 152172Hom.: 0 Cov.: 33
GnomAD3 genomes
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GnomAD3 exomes AF: 0.00155 AC: 388AN: 250774Hom.: 0 AF XY: 0.00152 AC XY: 206AN XY: 135714
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GnomAD4 exome AF: 0.00263 AC: 3842AN: 1461608Hom.: 9 Cov.: 31 AF XY: 0.00256 AC XY: 1858AN XY: 727100
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GnomAD4 genome ? AF: 0.00177 AC: 269AN: 152290Hom.: 0 Cov.: 33 AF XY: 0.00149 AC XY: 111AN XY: 74468
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Orthostatic hypotension 1 Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Dec 09, 2023 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Sep 02, 2022 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 25450229, 22028891) - |
DBH-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Mar 14, 2022 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
D
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D
M_CAP
Uncertain
D
MetaRNN
Benign
T
MetaSVM
Uncertain
T
MutationAssessor
Pathogenic
M
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D
REVEL
Pathogenic
Sift
Uncertain
D
Sift4G
Benign
T
Polyphen
P
Vest4
MutPred
Loss of glycosylation at T477 (P = 0.1173);
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at