chr10-70883952-A-G
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP5BP4
The NM_000281.4(PCBD1):c.313T>C(p.Ter105GlnextTer14) variant causes a stop lost change. The variant allele was found at a frequency of 0.0000123 in 1,461,378 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 32)
Exomes 𝑓: 0.000012 ( 0 hom. )
Consequence
PCBD1
NM_000281.4 stop_lost
NM_000281.4 stop_lost
Scores
1
2
4
Clinical Significance
Conservation
PhyloP100: 4.42
Genes affected
PCBD1 (HGNC:8646): (pterin-4 alpha-carbinolamine dehydratase 1) This gene encodes a member of the pterin-4-alpha-carbinolamine dehydratase family. The encoded protein has been identified as a moonlighting protein based on its ability to perform mechanistically distinct functions. The encoded protein functions as both a dehydratase involved in tetrahydrobiopterin biosynthesis, and as a cofactor for HNF1A-dependent transcription. A deficiency of this enzyme leads to hyperphenylalaninemia. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2014]
SGPL1 (HGNC:10817): (sphingosine-1-phosphate lyase 1) Enables sphinganine-1-phosphate aldolase activity. Involved in apoptotic signaling pathway; fatty acid metabolic process; and sphingolipid metabolic process. Located in endoplasmic reticulum. Implicated in nephrotic syndrome type 14. [provided by Alliance of Genome Resources, Apr 2022]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 2 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 10-70883952-A-G is Pathogenic according to our data. Variant chr10-70883952-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 428616.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Uncertain_significance=1}.
BP4
?
Computational evidence support a benign effect (BayesDel_addAF=-0.189829).. Strength limited to SUPPORTING due to the PP5.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PCBD1 | NM_000281.4 | c.313T>C | p.Ter105GlnextTer14 | stop_lost | 4/4 | ENST00000299299.4 | |
PCBD1 | NM_001289797.2 | c.166T>C | p.Ter56GlnextTer14 | stop_lost | 4/4 | ||
PCBD1 | NM_001323004.2 | c.216+1200T>C | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PCBD1 | ENST00000299299.4 | c.313T>C | p.Ter105GlnextTer14 | stop_lost | 4/4 | 1 | NM_000281.4 | P1 | |
SGPL1 | ENST00000697988.1 | c.571-9807A>G | intron_variant | ||||||
PCBD1 | ENST00000493228.1 | n.712T>C | non_coding_transcript_exon_variant | 4/4 | 2 | ||||
PCBD1 | ENST00000493961.5 | n.183+1200T>C | intron_variant, non_coding_transcript_variant | 2 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
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32
GnomAD3 exomes AF: 0.00000399 AC: 1AN: 250456Hom.: 0 AF XY: 0.00000739 AC XY: 1AN XY: 135338
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GnomAD4 exome AF: 0.0000123 AC: 18AN: 1461378Hom.: 0 Cov.: 35 AF XY: 0.0000124 AC XY: 9AN XY: 726886
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GnomAD4 genome ? Cov.: 32
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Pterin-4 alpha-carbinolamine dehydratase 1 deficiency Pathogenic:1Uncertain:1
Pathogenic, criteria provided, single submitter | research | National Reference Laboratory of Biochemistry, Pasteur Institute of Iran | Jan 01, 2015 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jul 05, 2022 | 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. ClinVar contains an entry for this variant (Variation ID: 428616). This protein extension has been observed in individual(s) with clinical features of biopterin-deficient hyperphenylalaninemia (PMID: 24133926, 27246466). This variant is present in population databases (rs770334825, gnomAD 0.003%). This sequence change disrupts the translational stop signal of the PCBD1 mRNA. It is expected to extend the length of the PCBD1 protein by 14 additional amino acid residues. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Benign
Dann
Benign
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
N
Vest4
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
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