12-102846948-T-C
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong
The NM_000277.3(PAH):c.916A>G(p.Ile306Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000285 in 1,613,220 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 (★★★).
Frequency
Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000028 ( 0 hom. )
Consequence
PAH
NM_000277.3 missense
NM_000277.3 missense
Scores
8
8
3
Clinical Significance
Conservation
PhyloP100: 7.67
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 16 ACMG points.
PM1
?
In a hotspot region, there are 13 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000277.3
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.939
PP5
?
Variant 12-102846948-T-C is Pathogenic according to our data. Variant chr12-102846948-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 618.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr12-102846948-T-C is described in Lovd as [Pathogenic]. Variant chr12-102846948-T-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PAH | NM_000277.3 | c.916A>G | p.Ile306Val | missense_variant | 9/13 | ENST00000553106.6 | |
PAH | NM_001354304.2 | c.916A>G | p.Ile306Val | missense_variant | 10/14 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PAH | ENST00000553106.6 | c.916A>G | p.Ile306Val | missense_variant | 9/13 | 1 | NM_000277.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000329 AC: 5AN: 152164Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251236Hom.: 0 AF XY: 0.0000295 AC XY: 4AN XY: 135772
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GnomAD4 exome AF: 0.0000281 AC: 41AN: 1461056Hom.: 0 Cov.: 30 AF XY: 0.0000344 AC XY: 25AN XY: 726924
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:9Other:1
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Phenylketonuria Pathogenic:7
Pathogenic, reviewed by expert panel | curation | ClinGen PAH Variant Curation Expert Panel | Aug 10, 2018 | PAH-specific ACMG/AMP criteria applied: PM2: MAF = 2.0e-5; PP3: Software agrees on a damaging effect.; PS3: Mutation ID#1, 18% residual enzyme activity (PMID:18590700); PM3: I306V / F55L (pathogenic in ClinVar) in a single patient with mild HPA (PMID:18299955); PP4_Moderate: BH4 defect excluded in all patients--single patient with mild hyperphe (Bercovich, 2008). (PMID:18299955). 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: (PM2, PP3, PS3, PM3, PP4_Moderate). - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 22, 2017 | Variant summary: The PAH c.916A>G (p.Ile306Val) variant involves the alteration of a conserved nucleotide. 4/5 in silico tools predict a damaging outcome for this variant. This variant was found in 1/121200 control chromosomes at a frequency of 0.0000083, which does not exceed the estimated maximal expected allele frequency of a pathogenic PAH variant (0.0079057). The variant was reported in numerous individuals in the literature, mainly associated with mild-PKU or hyperphenylalaninemia. In addition, in vitro assays show the variant to result in reduced PAH activity. Multiple clinical diagnostic laboratories/reputable databases classified this variant as likely pathogenic/pathogenic. Taken together, this variant is classified as pathogenic. - |
Pathogenic, no assertion criteria provided | clinical testing | Counsyl | Jan 21, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 18, 2024 | This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 306 of the PAH protein (p.Ile306Val). This variant is present in population databases (rs62642934, gnomAD 0.003%). This missense change has been observed in individuals with PAH-related disease (PMID: 1358789, 18299955, 23430547, 23764561). ClinVar contains an entry for this variant (Variation ID: 618). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PAH protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects PAH function (PMID: 11161839, 17924342, 25596310). For these reasons, this variant has been classified as Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | May 18, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Aug 26, 2023 | - - |
not provided Pathogenic:1Other:1
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jun 01, 2019 | - - |
not provided, no classification provided | literature only | DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE | - | - - |
Hyperphenylalaninemia Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 01, 1992 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Uncertain
Dann
Uncertain
DEOGEN2
Pathogenic
D;D
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D
MetaSVM
Pathogenic
D
MutationAssessor
Uncertain
M;.
MutationTaster
Benign
A;A
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N
REVEL
Pathogenic
Sift
Uncertain
D;D
Sift4G
Uncertain
D;D
Polyphen
P;.
Vest4
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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Calibrated prediction
Score
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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