rs62514956
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000277.3(PAH):c.912+1G>T variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 Pathogenic (★★★).
Frequency
Consequence
NM_000277.3 splice_donor, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PAH | NM_000277.3 | c.912+1G>T | splice_donor_variant, intron_variant | Intron 8 of 12 | ENST00000553106.6 | NP_000268.1 | ||
PAH | NM_001354304.2 | c.912+1G>T | splice_donor_variant, intron_variant | Intron 9 of 13 | NP_001341233.1 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 30
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Phenylketonuria Pathogenic:1
The c.912+1G>T variant is a canonical splice donor in PAH in which exon skipping disrupts the reading frame and is predicted to undergo nonsense mediated-decay. This variant was identified in 1 patient with PAH deficiency in a Catalonian cohort (PMID 10598814). This variant is absent from population databases. In summary, c.912+1G>T in PAH meets criteria to be classified as pathogenic. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, and PP4. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at