3-136250563-G-A
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5
The NM_000532.5(PCCB):c.183+5G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000412 in 1,457,486 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000532.5 splice_region, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PCCB | NM_000532.5 | c.183+5G>A | splice_region_variant, intron_variant | Intron 1 of 14 | ENST00000251654.9 | NP_000523.2 | ||
PCCB | NM_001178014.2 | c.183+5G>A | splice_region_variant, intron_variant | Intron 1 of 15 | NP_001171485.1 | |||
PCCB | XM_011512873.2 | c.183+5G>A | splice_region_variant, intron_variant | Intron 1 of 10 | XP_011511175.1 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 exomes AF: 0.00000427 AC: 1AN: 234344Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 129136
GnomAD4 exome AF: 0.00000412 AC: 6AN: 1457486Hom.: 0 Cov.: 31 AF XY: 0.00000690 AC XY: 5AN XY: 724808
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Propionic acidemia Pathogenic:3
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This sequence change falls in intron 1 of the PCCB gene. It does not directly change the encoded amino acid sequence of the PCCB protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (no rsID available, gnomAD 0.003%). This variant has been observed in individual(s) with propionic acidemia (PMID: 27227689). ClinVar contains an entry for this variant (Variation ID: 217896). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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. -
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at