12-102839204-G-A
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PM5PP3_ModeratePP5
The NM_000277.3(PAH):c.1330C>T(p.Leu444Phe) variant causes a missense change. The variant allele was found at a frequency of 0.0000093 in 1,613,736 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L444P) has been classified as Pathogenic.
Frequency
Consequence
NM_000277.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PAH | NM_000277.3 | c.1330C>T | p.Leu444Phe | missense_variant | Exon 13 of 13 | ENST00000553106.6 | NP_000268.1 | |
PAH | NM_001354304.2 | c.1330C>T | p.Leu444Phe | missense_variant | Exon 14 of 14 | NP_001341233.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152152Hom.: 0 Cov.: 33
GnomAD4 exome AF: 0.00000958 AC: 14AN: 1461584Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2AN XY: 727098
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152152Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74322
ClinVar
Submissions by phenotype
Phenylketonuria Pathogenic:2Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Mar 29, 2017 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 12, 2024 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 07, 2024 | This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 444 of the PAH protein (p.Leu444Phe). This variant is present in population databases (no rsID available, gnomAD 0.007%). This missense change has been observed in individual(s) with hyperphenylalaninemia (PMID: 26600521). 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: 551287). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt PAH protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at