rs1226613045
Variant summary
Our verdict is Pathogenic. Variant got 22 ACMG points: 22P and 0B. PVS1PM2PP3_StrongPP5_Very_Strong
The NM_000277.3(PAH):c.169-2A>G variant causes a splice acceptor change. The variant allele was found at a frequency of 0.00000137 in 1,456,302 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
PAH
NM_000277.3 splice_acceptor
NM_000277.3 splice_acceptor
Scores
5
1
1
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 7.13
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 22 ACMG points.
PVS1
?
Splicing variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 4.5, offset of 35, new splice context is: ctgacccacattgaatctAGacc. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
?
Variant 12-102894920-T-C is Pathogenic according to our data. Variant chr12-102894920-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 555212.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr12-102894920-T-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PAH | NM_000277.3 | c.169-2A>G | splice_acceptor_variant | ENST00000553106.6 | |||
LOC124902999 | XR_007063428.1 | n.863-9778T>C | intron_variant, non_coding_transcript_variant | ||||
PAH | NM_001354304.2 | c.169-2A>G | splice_acceptor_variant | ||||
PAH | XM_017019370.2 | c.169-2A>G | splice_acceptor_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PAH | ENST00000553106.6 | c.169-2A>G | splice_acceptor_variant | 1 | NM_000277.3 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
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32
GnomAD3 exomes AF: 0.00000799 AC: 2AN: 250224Hom.: 0 AF XY: 0.00000739 AC XY: 1AN XY: 135324
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GnomAD4 exome AF: 0.00000137 AC: 2AN: 1456302Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1AN XY: 724802
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GnomAD4 genome ? Cov.: 32
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:7
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Phenylketonuria Pathogenic:7
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 11, 2022 | For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site results in activation of a cryptic splice site and introduces a premature termination codon (PMID: 20188615). The resulting mRNA is expected to undergo nonsense-mediated decay. Studies have shown that disruption of this splice site alters PAH gene expression (PMID: 20188615). ClinVar contains an entry for this variant (Variation ID: 555212). This variant is also known as c.168-2A>G. Disruption of this splice site has been observed in individual(s) with hyperphenylalaninemia (PMID: 20188615, 29499199, 32668217). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (no rsID available, gnomAD 0.006%). This sequence change affects an acceptor splice site in intron 2 of the PAH gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. - |
Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Nov 29, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | This invariant splice site c.169-2A>G has been detected in the homozygous form in proband with classic Phenylketonuria (PKU) (Ho G et al). This variant has allele frequency of 0.00080% in the gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Dec 04, 2020 | - - |
Pathogenic, reviewed by expert panel | curation | ClinGen PAH Variant Curation Expert Panel | Aug 26, 2019 | The c.169-2A>G variant has been identified in at least 1 proband with classic PKU (PMID: 24368688). It has been detected in the homozygous form (PMID: 20188615) as well as in trans with the pathogenic variant Gly272Ter (PMID: 24368688). This variant is present at very low allele frequencies; 0.000007993 overall in gnomAD with a MAF of 0.00003267 (1/30612) in the South Asian population. Computational analysis predicts an alteration of the WT acceptor site, most probably affecting splicing, generating a frameshift, and leading to nonsense mediated decay. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM3, PM2, PP1_Moderate, PP4. - |
Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Oct 19, 2020 | Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with phenylketonuria (PKU) (MIM#261600). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0210 - Splice site variant proven to affect splicing of the transcript with a known effect on protein sequence (p.(Glu57Valfs*13)). Analysis of patient cells concludes this variant introduces the use of an upstream cryptic acceptor splice site in intron two, resulting in retention of intronic sequence, a frameshift and a premature termination codon (PMID: 20188615). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD v2 <0.01 for a recessive condition (2 heterozygotes,0 homozygotes). (SP) 0703 - Another splice variant comparable to the one identified in this case has moderate previous evidence for pathogenicity. A splice variant at the same intron junction (c.169-13T>G) has been reported several times as pathogenic in patients with PKU (ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported multiple times as pathogenic (ClinVar), and has been observed in a homozygous family, and a compound heterozygous patient with PKU (ClinVar, PMID: 20188615, PMID: 24368688). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
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
Pathogenic
D
MutationTaster
Benign
D;D
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AL_spliceai
Position offset: -2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at