rs62642906
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000277.3(PAH):c.47_48del(p.Ser16Ter) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000805 in 1,614,084 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000075 ( 0 hom. )
Consequence
PAH
NM_000277.3 frameshift
NM_000277.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 1.82
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 does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 1159 pathogenic variants in the truncated region.
PM2
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Very rare variant in population databases, with high coverage;
PP5
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Variant 12-102917082-CAG-C is Pathogenic according to our data. Variant chr12-102917082-CAG-C is described in ClinVar as [Pathogenic]. Clinvar id is 102696.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr12-102917082-CAG-C is described in Lovd as [Pathogenic]. Variant chr12-102917082-CAG-C is described in Lovd as [Pathogenic]. Variant chr12-102917082-CAG-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PAH | NM_000277.3 | c.47_48del | p.Ser16Ter | frameshift_variant | 1/13 | ENST00000553106.6 | |
PAH | NM_001354304.2 | c.47_48del | p.Ser16Ter | frameshift_variant | 2/14 | ||
PAH | XM_017019370.2 | c.47_48del | p.Ser16Ter | frameshift_variant | 1/7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PAH | ENST00000553106.6 | c.47_48del | p.Ser16Ter | frameshift_variant | 1/13 | 1 | NM_000277.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152216Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251444Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135902
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GnomAD4 exome AF: 0.00000752 AC: 11AN: 1461868Hom.: 0 AF XY: 0.00000550 AC XY: 4AN XY: 727230
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:11Other:1
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Phenylketonuria Pathogenic:9
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 31, 2023 | - - |
Likely pathogenic, criteria provided, single submitter | literature only | Counsyl | Jan 26, 2015 | - - |
Pathogenic, reviewed by expert panel | curation | ClinGen PAH Variant Curation Expert Panel | Aug 10, 2018 | PAH-specific ACMG/AMP criteria applied: PM2: ExAC:8.238e-06; gnomAD:0.000004062; 1000G + ESP: absent; PVS1: Null variant- frameshift. Subject to nonsense mediated decay.; PM3: found in trans with L48S (VarID608, Pathogenic) (PMID:8535445); PP4: 47delCT found in 1 patient with moderate PKU. BH4 deficiency not ruled out. (PMID:8535445). 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, PVS1, PM3, PP4). - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | DASA | Mar 05, 2022 | The c.47_48delCT;p.(Ser16*) variant creates a premature translational stop signal in the PAH gene. It is expected to result in an absent or disrupted protein product - PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 10269; PMID: 8535445; PMID: 10394930; PMID: 16198137; PMID: 17096675; PMID: 21147011; PMID: 21890392; PMID: 263224156) - PS4. This variant is not present in population databases (rs62642906- gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. The p.(Ser16*) was detected in trans with a pathogenic variant (PMID:8535445) - PM3. In summary, the currently available evidence indicates that the variant is pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 21, 2023 | This sequence change creates a premature translational stop signal (p.Ser16*) 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 (rs62642906, gnomAD 0.0009%). This premature translational stop signal has been observed in individuals with hyperphenylalaninemia and phenylketonuria (PMID: 8535445, 10394930, 16198137, 17096675, 21147011, 21890392, 26322415). This variant is also known as c.44_45delTC, p.Ser16fs. ClinVar contains an entry for this variant (Variation ID: 102696). 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, no assertion criteria provided | clinical testing | Zotz-Klimas Genetics Lab, MVZ Zotz Klimas | Oct 30, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 25, 2019 | Variant summary: PAH c.47_48delCT (p.Ser16X) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory (c.165delT, p.Phe55fsX6; c.331C>T, p.Arg111X; c.556delA, p.Thr186fsX9). The variant allele was found at a frequency of 4.1e-06 in 246214 control chromosomes (gnomAD). This variant has been reported in the literature in multiple individuals affected with Phenylalanine Hydroxylase Deficiency (Aldamiz-Echevarria_2016, Ramus_1995, Tao_2015, Trunzo_2015, Wang_2017). These data indicate that the variant is very likely to be associated with disease. In vitro expression experiment reports that PAH residual activity for this variant effect results in <10% of normal activity (Aldamiz-Echevarria_2016). Three ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as likely pathogenic/pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, no assertion criteria provided | clinical testing | Neonatal Disease Screening Center, Medical Genetics Center, Huaihua City Maternal and Child Health Care Hospital | - | PVS1+PM2+PM3_S+PP4_M - |
not provided Pathogenic:2Other:1
not provided, no classification provided | literature only | DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 16, 2023 | Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 21890392, 12655550, 12655553, 23357515, 8535445, 19444284, 16879198, 23430918, 17935162, 23430547, 21147011, 19062537, 10394930, 31589614, 29499199, 32668217, 35405047) - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Apr 02, 2014 | - - |
Computational scores
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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