rs62517166
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM3_SupportingPVS1PP4_ModeratePM2
This summary comes from the ClinGen Evidence Repository: The c.441+1G>C variant in PAH is a canonical splice-site variant predicted to result in skipping of exon 5, leading to a frameshift, premature protein truncation, and NMD (PVS1). It is present at an extremely low frequency in gnomAD (MAF = 0.00000398, less than the 0.0002 MAF cutoff) (PM2) and absent from other ethnically diverse control databases, including 1000 Genomes and ESP (PM2). It is reported Likely Pathogenic in Clinvar (Variation ID 556894) by one diagnostic testing lab. It has been reported in the published literature in a Kurdish patient with classic PKU (PMID:24048906), diagnosed by plasma Phe levels; BH4 deficiency was excluded by urinary pterin analysis (PP4_Moderate). The patient was homozygous for the variant (PMID:24048906) (PM3_Supporting). Classification: PathogenicSupporting Criteria: PVS1, PM2, PM3_Supporting, PP4_Moderate LINK:https://erepo.genome.network/evrepo/ui/classification/CA6748955/MONDO:0009861/006
Frequency
Consequence
NM_000277.3 splice_donor
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 13 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PAH | NM_000277.3 | c.441+1G>C | splice_donor_variant | ENST00000553106.6 | |||
LOC124902999 | XR_007063428.1 | n.808-2418C>G | intron_variant, non_coding_transcript_variant | ||||
PAH | NM_001354304.2 | c.441+1G>C | splice_donor_variant | ||||
PAH | XM_017019370.2 | c.441+1G>C | splice_donor_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PAH | ENST00000553106.6 | c.441+1G>C | splice_donor_variant | 1 | NM_000277.3 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251482Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135914
GnomAD4 exome AF: 6.85e-7 AC: 1AN: 1459438Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 726224
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Phenylketonuria Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Feb 26, 2018 | - - |
Pathogenic, reviewed by expert panel | curation | ClinGen PAH Variant Curation Expert Panel | Apr 05, 2020 | The c.441+1G>C variant in PAH is a canonical splice-site variant predicted to result in skipping of exon 5, leading to a frameshift, premature protein truncation, and NMD (PVS1). It is present at an extremely low frequency in gnomAD (MAF = 0.00000398, less than the 0.0002 MAF cutoff) (PM2) and absent from other ethnically diverse control databases, including 1000 Genomes and ESP (PM2). It is reported Likely Pathogenic in Clinvar (Variation ID 556894) by one diagnostic testing lab. It has been reported in the published literature in a Kurdish patient with classic PKU (PMID: 24048906), diagnosed by plasma Phe levels; BH4 deficiency was excluded by urinary pterin analysis (PP4_Moderate). The patient was homozygous for the variant (PMID: 24048906) (PM3_Supporting). Classification: Pathogenic Supporting Criteria: PVS1, PM2, PM3_Supporting, PP4_Moderate - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at