rs1057516914
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PP4PM3_SupportingPM2PVS1
This summary comes from the ClinGen Evidence Repository: The c.745del (p.Leu249fs) variant in PAH has been reported in 1 Chilean patient with mild PKU; Phe = 600-900umol/L (PMID:29288420; PP4). This variant was detected with V388M - reported at Pathogenic in ClinVar (VarID:610, 7 submitters); phase not confirmed - 0.5 points (PMID:29288420; PM3_supporting). This frameshift variant is predicted to undergo NMD, not located in last exon or last 50bp of preliminary exon (Coding exon number 7 out of 13 coding exons; 7 out of total exons) (PVS1). This variant is absent from population databases (PM2). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PP4, PM3_supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA16020850/MONDO:0009861/006
Frequency
Consequence
NM_000277.3 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PAH | NM_000277.3 | c.745del | p.Leu249PhefsTer92 | frameshift_variant | 7/13 | ENST00000553106.6 | |
PAH | NM_001354304.2 | c.745del | p.Leu249PhefsTer92 | frameshift_variant | 8/14 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PAH | ENST00000553106.6 | c.745del | p.Leu249PhefsTer92 | frameshift_variant | 7/13 | 1 | NM_000277.3 | P1 | |
PAH | ENST00000307000.7 | c.730del | p.Leu244PhefsTer92 | frameshift_variant | 8/14 | 5 | |||
PAH | ENST00000549247.6 | n.504del | non_coding_transcript_exon_variant | 1/6 | 2 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 31
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Phenylketonuria Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Aug 29, 2022 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | May 27, 2016 | - - |
Pathogenic, reviewed by expert panel | curation | ClinGen PAH Variant Curation Expert Panel | May 15, 2021 | The c.745del (p.Leu249fs) variant in PAH has been reported in 1 Chilean patient with mild PKU; Phe = 600-900umol/L (PMID: 29288420; PP4). This variant was detected with V388M - reported at Pathogenic in ClinVar (VarID:610, 7 submitters); phase not confirmed - 0.5 points (PMID: 29288420; PM3_supporting). This frameshift variant is predicted to undergo NMD, not located in last exon or last 50bp of preliminary exon (Coding exon number 7 out of 13 coding exons; 7 out of total exons) (PVS1). This variant is absent from population databases (PM2). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PP4, PM3_supporting. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at