rs972937270
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1_ModeratePM2PP3_StrongPP5_Very_Strong
The NM_000282.4(PCCA):c.231+1G>C variant causes a splice donor change. The variant allele was found at a frequency of 0.00000497 in 1,610,276 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/2 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000041 ( 0 hom. )
Consequence
PCCA
NM_000282.4 splice_donor
NM_000282.4 splice_donor
Scores
5
1
1
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 6.26
Genes affected
PCCA (HGNC:8653): (propionyl-CoA carboxylase subunit alpha) The protein encoded by this gene is the alpha subunit of the heterodimeric mitochondrial enzyme Propionyl-CoA carboxylase. PCCA encodes the biotin-binding region of this enzyme. Mutations in either PCCA or PCCB (encoding the beta subunit) lead to an enzyme deficiency resulting in propionic acidemia. Multiple transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, May 2010]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 16 ACMG points.
PVS1
?
Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.021490626 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
?
Variant 13-100111889-G-C is Pathogenic according to our data. Variant chr13-100111889-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 550113.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-100111889-G-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PCCA | NM_000282.4 | c.231+1G>C | splice_donor_variant | ENST00000376285.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PCCA | ENST00000376285.6 | c.231+1G>C | splice_donor_variant | 1 | NM_000282.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000132 AC: 2AN: 152048Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000798 AC: 2AN: 250554Hom.: 0 AF XY: 0.00000738 AC XY: 1AN XY: 135522
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GnomAD4 exome AF: 0.00000411 AC: 6AN: 1458228Hom.: 0 Cov.: 29 AF XY: 0.00000276 AC XY: 2AN XY: 725660
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Propionic acidemia Pathogenic:5
Likely pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Nov 11, 2021 | NM_000282.3(PCCA):c.231+1G>C is a canonical splice site variant classified as likely pathogenic in the context of PCCA-related propionic acidemia. c.231+1G>C has been observed in cases with relevant disease (PMID: 22033733, 25047749). Functional assessments of this variant are available in the literature (PMID: 19157943). Internal structural analysis of the variant is supportive of pathogenicity. c.231+1G>C has been observed in population frequency databases (gnomAD: NFE 0.01%). In summary, NM_000282.3(PCCA):c.231+1G>C is a canonical splice site variant that has both functional and internal structural support for pathogenicity and has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 28, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Sep 21, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 19, 2018 | Variant summary: PCCA c.231+1G>C is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5' splicing donor site. One publication reports experimental evidence that this variant determines exons 3-4 skipping (Desviat_2009). The variant allele was found at a frequency of 1.4e-05 in 276520 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in PCCA causing Propionic Acidemia (1.4e-05 vs 0.0034), allowing no conclusion about variant significance. The c.231+1G>C variant has been reported in the literature in individuals affected with Propionic Acidemia (Desviat_2006, Desviat_2009). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 14, 2022 | For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 550113). Disruption of this splice site has been observed in individuals with propionic acidemia (PMID: 22033733, 25047749). This variant is present in population databases (no rsID available, gnomAD 0.008%). This sequence change affects a donor splice site in intron 3 of the PCCA gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in PCCA are known to be pathogenic (PMID: 15464417). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
D;D;D
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
Position offset: -1
Find out detailed SpliceAI scores and Pangolin per-transcript scores at