12-102852815-G-C
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PM5PP3_StrongPP5_Moderate
The NM_000277.3(PAH):c.842C>G(p.Pro281Arg) variant causes a missense, splice region 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 predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P281A) has been classified as Pathogenic.
Frequency
Consequence
NM_000277.3 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PAH | NM_000277.3 | c.842C>G | p.Pro281Arg | missense_variant, splice_region_variant | Exon 7 of 13 | ENST00000553106.6 | NP_000268.1 | |
PAH | NM_001354304.2 | c.842C>G | p.Pro281Arg | missense_variant, splice_region_variant | Exon 8 of 14 | NP_001341233.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PAH | ENST00000553106.6 | c.842C>G | p.Pro281Arg | missense_variant, splice_region_variant | Exon 7 of 13 | 1 | NM_000277.3 | ENSP00000448059.1 | ||
PAH | ENST00000307000.7 | c.827C>G | p.Pro276Arg | missense_variant, splice_region_variant | Exon 8 of 14 | 5 | ENSP00000303500.2 | |||
PAH | ENST00000635477.1 | c.2C>G | p.Pro1Arg | missense_variant, splice_region_variant | Exon 1 of 6 | 5 | ENSP00000489230.1 | |||
PAH | ENST00000549247.6 | n.601C>G | splice_region_variant, non_coding_transcript_exon_variant | Exon 1 of 6 | 2 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 31
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Phenylketonuria Pathogenic:1
This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects PAH function (PMID: 9450897). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Not Available"). This missense change has been observed in individual(s) with hyperphenylalaninemia (PMID: 12409276, 21147011, 27264808). This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 281 of the PAH protein (p.Pro281Arg). -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
No publications associated with this variant yet.