rs752761437
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.1284+1G>A variant causes a splice donor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000903 in 1,550,532 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_000282.4 splice_donor
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PCCA | NM_000282.4 | c.1284+1G>A | splice_donor_variant | ENST00000376285.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PCCA | ENST00000376285.6 | c.1284+1G>A | splice_donor_variant | 1 | NM_000282.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000723 AC: 11AN: 152126Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000358 AC: 9AN: 251288Hom.: 0 AF XY: 0.0000442 AC XY: 6AN XY: 135798
GnomAD4 exome AF: 0.0000922 AC: 129AN: 1398406Hom.: 0 Cov.: 23 AF XY: 0.0000972 AC XY: 68AN XY: 699678
GnomAD4 genome ? AF: 0.0000723 AC: 11AN: 152126Hom.: 0 Cov.: 33 AF XY: 0.0000673 AC XY: 5AN XY: 74316
ClinVar
Submissions by phenotype
Propionic acidemia Pathogenic:7
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 16, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jan 20, 2024 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Counsyl | Oct 19, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 07, 2020 | Variant summary: PCCA c.1284+1G>A 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 canonical 5' splicing donor site. At least one publication confirmed this prediction by reporting RT-PCR analysis of patient derived mRNA that revealed skipping of exons 13 and 14 (V356_G428del73) (Campeau_2001). The variant allele was found at a frequency of 3.6e-05 in 251288 control chromosomes. c.1284+1G>A has been reported in the literature in individuals affected with Propionic Acidemia (example, Campeau_2001, Vatanavicharn_2014, Cappuccio_2016, Longo_2017). These data indicate that the variant is likely to 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 propionyl-CoA carboxylase activity in a patient with a compound heterozygous genotype (Longo_2017). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (n=3)/likely pathogenic(n=1). Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Aug 25, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 07, 2024 | This sequence change affects a donor splice site in intron 14 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). This variant is present in population databases (rs752761437, gnomAD 0.006%). Disruption of this splice site has been observed in individuals with propionic acidemia (PMID: 24464666, 27900673, 28712602). ClinVar contains an entry for this variant (Variation ID: 279863). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Oct 25, 2018 | The PCCA c.1284+1G>A variant occurs in a canonical splice site (donor) and is therefore predicted to disrupt or distort the normal gene product. The c.1284+1G>A variant has been reported in four studies in which it is found in four individuals with propionic academia, including in one in a homozygous state, in two in a compound heterozygous state, and in one in a heterozygous state (Campeau et al. 2001; Vatanavicharn et al. 2014; Cappuccio et al. 2016; Longo et al. 2017). Control data are unavailable for this variant, which is reported at a frequency of 0.00006 in the European (non-Finnish) population of the Genome Aggregation Database. RT-PCR analysis indicated that the c.1284+1G>A variant results in the skipping of exons 13 and 14 (Campeau et al. 2001). Based on the evidence and the potential impact of splice donor variants, the c.1284+1G>A variant is classified as likely pathogenic for propionic academia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
PCCA-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Nov 01, 2022 | The PCCA c.1284+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant has been reported in the homozygous or presumed compound heterozygous state in several patients with propionic acidemia (Vatanavicharn et al. 2014. PubMed ID: 24464666; Cappuccio et al. 2017. PubMed ID: 27900673; Longo et al. 2017. PubMed ID: 28712602). Based on RT-PCR analysis, this variant was reported to lead to skipping of exons 13 and 14 (Campeau et al. 2001. PubMed ID: 11592820, reported as IVS14+1G>A), which affects the biotin carboxylase domain (Vatanavicharn et al. 2014. PubMed ID: 24464666). This variant is reported in 0.0070% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/13-100955253-G-A). Based on the collective evidence, we classify this variant as pathogenic. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 19, 2018 | The c.1284+1G>A pathogenic variant in the PCCA gene has been reported previously in the homozygous state in an individual with propionic acidemia (Vatanavicharn et al., 2014). This splice site variant destroys the canonical splice donor site in intron 14. It is predicted to cause abnormal gene splicing, either leading to an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. The c.1284+1G>A variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret c.1284+1G>A as a pathogenic variant. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at