rs775563122
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong
The NM_000532.5(PCCB):c.1402G>A(p.Ala468Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000753 in 1,460,770 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A468S) has been classified as Uncertain significance.
Frequency
Consequence
NM_000532.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PCCB | NM_000532.5 | c.1402G>A | p.Ala468Thr | missense_variant | 14/15 | ENST00000251654.9 | |
PCCB | NM_001178014.2 | c.1462G>A | p.Ala488Thr | missense_variant | 15/16 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PCCB | ENST00000251654.9 | c.1402G>A | p.Ala468Thr | missense_variant | 14/15 | 1 | NM_000532.5 | P2 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251050Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135642
GnomAD4 exome AF: 0.00000753 AC: 11AN: 1460770Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4AN XY: 726816
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Propionic acidemia Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Mar 07, 2018 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | The PCCB c.1402G>A (p.Ala468Thr) missense variant has been identified in a compound heterozygous state in one individual with mild propionic acidemia (Yorifuji et al. 2002). Control data are unavailable for this variant, which is reported at a frequency of 0.00002 in the European (non-Finnish) population of the Exome Aggregation Consortium, but this is based on one allele in a region of good sequence coverage so the variant is presumed to be rare. When analyzed in vivo, the p.Ala468Thr variant was found to have 5.49% of wildtype PCC activity. The evidence for this variant is limited. The p.Ala468Thr variant is therefore classified as a variant of unknown significance but suspicious for pathogenicity for propionic acidemia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at