chr12-102852924-C-T
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM3_StrongPM5PM2PP3PP4
This summary comes from the ClinGen Evidence Repository: The c.733G>A (p.Val245Met) variant in PAH has been reported in 2 individuals with PAH deficiency, detected in trans with pathogenic variants p.E178G (PMID:26542770) and c.913-7A>G (PMID:29316886). This variant is absent in population databases. Other missense variants at this same amino acid are interpreted as pathogenic (p.V245A, p.V245L, p.V245E). Computational prediction tools and conservation analysis support a deleterious effect. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_strong, PM2, PM5, PP4, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA229722/MONDO:0009861/006
Frequency
Consequence
ENST00000553106.6 missense
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/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PAH | NM_000277.3 | c.733G>A | p.Val245Met | missense_variant | 7/13 | ENST00000553106.6 | NP_000268.1 | |
PAH | NM_001354304.2 | c.733G>A | p.Val245Met | missense_variant | 8/14 | NP_001341233.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PAH | ENST00000553106.6 | c.733G>A | p.Val245Met | missense_variant | 7/13 | 1 | NM_000277.3 | ENSP00000448059 | P1 | |
PAH | ENST00000307000.7 | c.718G>A | p.Val240Met | missense_variant | 8/14 | 5 | ENSP00000303500 | |||
PAH | ENST00000549247.6 | n.492G>A | non_coding_transcript_exon_variant | 1/6 | 2 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 32
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Phenylketonuria Pathogenic:1
Pathogenic, reviewed by expert panel | curation | ClinGen PAH Variant Curation Expert Panel | Nov 10, 2020 | The c.733G>A (p.Val245Met) variant in PAH has been reported in 2 individuals with PAH deficiency, detected in trans with pathogenic variants p.E178G (PMID: 26542770) and c.913-7A>G (PMID: 29316886). This variant is absent in population databases. Other missense variants at this same amino acid are interpreted as pathogenic (p.V245A, p.V245L, p.V245E). Computational prediction tools and conservation analysis support a deleterious effect. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_strong, PM2, PM5, PP4, PP3. - |
not provided Other:1
not provided, no classification provided | literature only | DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at