rs202247815
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_000282.4(PCCA):āc.491T>Cā(p.Ile164Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,613,766 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 Likely pathogenic (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I164V) has been classified as Likely benign.
Frequency
Consequence
NM_000282.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PCCA | NM_000282.4 | c.491T>C | p.Ile164Thr | missense_variant | 7/24 | ENST00000376285.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PCCA | ENST00000376285.6 | c.491T>C | p.Ile164Thr | missense_variant | 7/24 | 1 | NM_000282.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152186Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251380Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135844
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461462Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1AN XY: 727066
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152304Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74476
ClinVar
Submissions by phenotype
Propionic acidemia Pathogenic:2Other:1
not provided, no classification provided | literature only | GeneReviews | - | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 09, 2023 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jun 22, 2023 | Experimental studies have shown that this missense change affects PCCA function (PMID: 12385775). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. 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 PCCA protein function. ClinVar contains an entry for this variant (Variation ID: 38868). This variant is also known as 416T>C (Ile139Thr). This missense change has been observed in individual(s) with propionic Acidemia (PMID: 10101253, 11592820). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs202247815, gnomAD 0.003%). This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 164 of the PCCA protein (p.Ile164Thr). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at