rs375716771
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Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP3_ModeratePP5
The NM_001082971.2(DDC):c.923A>T(p.Asn308Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000682 in 1,613,220 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000068 ( 0 hom. )
Consequence
DDC
NM_001082971.2 missense
NM_001082971.2 missense
Scores
7
9
2
Clinical Significance
Conservation
PhyloP100: 7.15
Genes affected
DDC (HGNC:2719): (dopa decarboxylase) The encoded protein catalyzes the decarboxylation of L-3,4-dihydroxyphenylalanine (DOPA) to dopamine, L-5-hydroxytryptophan to serotonin and L-tryptophan to tryptamine. Defects in this gene are the cause of aromatic L-amino-acid decarboxylase deficiency (AADCD). AADCD deficiency is an inborn error in neurotransmitter metabolism that leads to combined serotonin and catecholamine deficiency. Multiple alternatively spliced transcript variants encoding different isoforms have been identified for this gene. [provided by RefSeq, Jun 2011]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 5 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.898
PP5
?
Variant 7-50495371-T-A is Pathogenic according to our data. Variant chr7-50495371-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 568083.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=2}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DDC | NM_001082971.2 | c.923A>T | p.Asn308Ile | missense_variant | 9/15 | ENST00000444124.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DDC | ENST00000444124.7 | c.923A>T | p.Asn308Ile | missense_variant | 9/15 | 1 | NM_001082971.2 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152226Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000239 AC: 6AN: 251344Hom.: 0 AF XY: 0.0000368 AC XY: 5AN XY: 135852
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GnomAD4 exome AF: 0.00000684 AC: 10AN: 1460994Hom.: 0 Cov.: 30 AF XY: 0.0000124 AC XY: 9AN XY: 726840
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Deficiency of aromatic-L-amino-acid decarboxylase Pathogenic:1Uncertain:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Mendelics | Jul 06, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 19, 2024 | This sequence change replaces asparagine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 308 of the DDC protein (p.Asn308Ile). This variant is present in population databases (no rsID available, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with DDC-related conditions. ClinVar contains an entry for this variant (Variation ID: 568083). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt DDC protein function with a positive predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Oct 31, 2022 | Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
D;.;T;.;.;.;D;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D
MetaSVM
Uncertain
T
MutationAssessor
Pathogenic
H;.;.;.;.;.;H;H
MutationTaster
Benign
D;D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;.;.;.;D;D;D;D
REVEL
Uncertain
Sift
Pathogenic
D;.;.;.;D;D;D;D
Sift4G
Uncertain
D;D;D;D;D;D;D;D
Polyphen
D;.;.;.;.;.;D;.
Vest4
MutPred
Loss of catalytic residue at N308 (P = 0.0138);.;.;.;.;.;Loss of catalytic residue at N308 (P = 0.0138);Loss of catalytic residue at N308 (P = 0.0138);
MVP
MPC
1.1
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
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