rs62508586
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PP3PP4PM3_SupportingPM2
This summary comes from the ClinGen Evidence Repository: The c.441+4A>G variant in PAH has been reported in an individual with PAH deficiency (PP4) with likely pathogenic variant p.Val230Ile (PM3-supporting) (PMID:12655553); and an Iranian patient with PAH deficiency ( PMID:28676969, 2nd variant not reported). This variant is absent in population databases (PM2). Computational evidence support a splicing effect (HSF and MaxEnt). In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PP4, PM2, PM3_supporting, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA229548/MONDO:0009861/006
Frequency
Consequence
NM_000277.3 splice_donor_region, intron
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.441+4A>G | splice_donor_region_variant, intron_variant | ENST00000553106.6 | |||
LOC124902999 | XR_007063428.1 | n.808-2421T>C | intron_variant, non_coding_transcript_variant | ||||
PAH | NM_001354304.2 | c.441+4A>G | splice_donor_region_variant, intron_variant | ||||
PAH | XM_017019370.2 | c.441+4A>G | splice_donor_region_variant, intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PAH | ENST00000553106.6 | c.441+4A>G | splice_donor_region_variant, intron_variant | 1 | NM_000277.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152098Hom.: 0 Cov.: 31
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1458484Hom.: 0 Cov.: 31 AF XY: 0.00000551 AC XY: 4AN XY: 725778
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152098Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 74300
ClinVar
Submissions by phenotype
Phenylketonuria Pathogenic:2Uncertain:2
Uncertain significance, reviewed by expert panel | curation | ClinGen PAH Variant Curation Expert Panel | Sep 29, 2019 | The c.441+4A>G variant in PAH has been reported in an individual with PAH deficiency (PP4) with likely pathogenic variant p.Val230Ile (PM3-supporting) (PMID: 12655553); and an Iranian patient with PAH deficiency ( PMID: 28676969, 2nd variant not reported). This variant is absent in population databases (PM2). Computational evidence support a splicing effect (HSF and MaxEnt). In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PP4, PM2, PM3_supporting, PP3. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Sep 07, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 23, 2023 | This sequence change falls in intron 4 of the PAH gene. It does not directly change the encoded amino acid sequence of the PAH protein. It affects a nucleotide within the consensus splice site. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with PAH-related conditions (PMID: 12655553, 19015950, 28676969; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 102674). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Nov 12, 2023 | - - |
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