rs76296470
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000277.3(PAH):c.331C>T(p.Arg111Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000552 in 1,613,768 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 Pathogenic (★★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000057 ( 0 hom. )
Consequence
PAH
NM_000277.3 stop_gained
NM_000277.3 stop_gained
Scores
4
2
1
Clinical Significance
Conservation
PhyloP100: 4.80
Genes affected
PAH (HGNC:8582): (phenylalanine hydroxylase) This gene encodes a member of the biopterin-dependent aromatic amino acid hydroxylase protein family. The encoded phenylalanine hydroxylase enzyme hydroxylates phenylalanine to tyrosine and is the rate-limiting step in phenylalanine catabolism. Deficiency of this enzyme activity results in the autosomal recessive disorder phenylketonuria. [provided by RefSeq, Aug 2017]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 12-102894756-G-A is Pathogenic according to our data. Variant chr12-102894756-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 581.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr12-102894756-G-A is described in Lovd as [Pathogenic]. Variant chr12-102894756-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PAH | NM_000277.3 | c.331C>T | p.Arg111Ter | stop_gained | 3/13 | ENST00000553106.6 | |
LOC124902999 | XR_007063428.1 | n.863-9942G>A | intron_variant, non_coding_transcript_variant | ||||
PAH | NM_001354304.2 | c.331C>T | p.Arg111Ter | stop_gained | 4/14 | ||
PAH | XM_017019370.2 | c.331C>T | p.Arg111Ter | stop_gained | 3/7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PAH | ENST00000553106.6 | c.331C>T | p.Arg111Ter | stop_gained | 3/13 | 1 | NM_000277.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000395 AC: 6AN: 152032Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000278 AC: 7AN: 251436Hom.: 0 AF XY: 0.0000294 AC XY: 4AN XY: 135882
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GnomAD4 exome AF: 0.0000568 AC: 83AN: 1461736Hom.: 0 Cov.: 31 AF XY: 0.0000591 AC XY: 43AN XY: 727182
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:12Other:1
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Phenylketonuria Pathogenic:9
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 12, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | This sequence change creates a premature translational stop signal (p.Arg111*) in the PAH gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PAH are known to be pathogenic (PMID: 1301187, 9634518). This variant is present in population databases (rs76296470, gnomAD 0.02%). This premature translational stop signal has been observed in individuals with phenylketonuria (PMID: 12542580, 16256386, 21307867, 24401910, 27121329). ClinVar contains an entry for this variant (Variation ID: 581). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Nov 20, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Mar 15, 2022 | - - |
Pathogenic, reviewed by expert panel | curation | ClinGen PAH Variant Curation Expert Panel | Aug 10, 2018 | PAH-specific ACMG/AMP criteria applied: PVS1: Nonsense variant; PP4_Moderate: Seen in multiple Chinese PKU patients. BH4 deficiency excluded. (PMID:1301187; PMID:2816939; PMID:9860305); PM3: Detected with R243Q, pathogenic in ClinVar (PMID:15503242). In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PVS1, PP4_Moderate, PM3). - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Counsyl | Jan 21, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 03, 2018 | Variant summary: PAH c.331C>T (p.Arg111X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 3.2e-05 in 246200 control chromosomes (gnomAD). The variant, c.331C>T, has been reported in the literature in multiple individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria)(Tao_2015, Tyfield_1995). These data indicate that the variant is very likely to be associated with disease. Three ClinVar submissions from other clinical diagnostic laboratories (evaluation after 2014) cites the variant as "pathogenic." Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | May 01, 1990 | - - |
not provided Pathogenic:3Other:1
Pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Feb 18, 2015 | - - |
not provided, no classification provided | literature only | DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
A;A
Vest4
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at