rs5030843
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PP3PM5PM2
This summary comes from the ClinGen Evidence Repository: The c.473G>C (p.Arg158Pro) variant in PAH was reported in PMID:22330942, but was listed as (p.Arg158Gln). Therefore, we are uncertain if the variant is c.473G>C, or p.Arg158Gln. This variant has an extremely low frequency in ExAC and gnomAD (MAF 0.00002). It is predicted deleterious in SIFT, Polyphen2, MutationTaster and REVEL=0.98. Two different pathogenic missense changes at this amino acid have been seen before (R158W, R158Q). In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM5, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA229571/MONDO:0009861/006
Frequency
Consequence
NM_000277.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PAH | NM_000277.3 | c.473G>C | p.Arg158Pro | missense_variant | 5/13 | ENST00000553106.6 | |
LOC124902999 | XR_007063428.1 | n.807+1405C>G | intron_variant, non_coding_transcript_variant | ||||
PAH | NM_001354304.2 | c.473G>C | p.Arg158Pro | missense_variant | 6/14 | ||
PAH | XM_017019370.2 | c.473G>C | p.Arg158Pro | missense_variant | 5/7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PAH | ENST00000553106.6 | c.473G>C | p.Arg158Pro | missense_variant | 5/13 | 1 | NM_000277.3 | P1 | |
PAH | ENST00000549111.5 | n.569G>C | non_coding_transcript_exon_variant | 5/6 | 1 | ||||
PAH | ENST00000307000.7 | c.458G>C | p.Arg153Pro | missense_variant | 6/14 | 5 | |||
PAH | ENST00000551988.5 | n.530+10830G>C | intron_variant, non_coding_transcript_variant | 3 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251364Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135846
GnomAD4 exome AF: 0.00000753 AC: 11AN: 1461516Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5AN XY: 727082
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Phenylketonuria Pathogenic:1Uncertain:1
Uncertain significance, reviewed by expert panel | curation | ClinGen PAH Variant Curation Expert Panel | Nov 09, 2019 | The c.473G>C (p.Arg158Pro) variant in PAH was reported in PMID: 22330942, but was listed as (p.Arg158Gln). Therefore, we are uncertain if the variant is c.473G>C, or p.Arg158Gln. This variant has an extremely low frequency in ExAC and gnomAD (MAF 0.00002). It is predicted deleterious in SIFT, Polyphen2, MutationTaster and REVEL=0.98. Two different pathogenic missense changes at this amino acid have been seen before (R158W, R158Q). In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM5, PP3. - |
Pathogenic, criteria provided, single submitter | clinical testing | Centre for Inherited Metabolic Diseases, Karolinska University Hospital | Feb 21, 2024 | - - |
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