rs62508613
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Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2PP5_Very_StrongBP4
The NM_000277.3(PAH):c.1199+17G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,613,152 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)
Exomes 𝑓: 0.0000021 ( 0 hom. )
Consequence
PAH
NM_000277.3 intron
NM_000277.3 intron
Scores
2
Clinical Significance
Conservation
PhyloP100: 0.586
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 Likely_pathogenic. Variant got 9 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 12-102843629-C-T is Pathogenic according to our data. Variant chr12-102843629-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 102555.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-102843629-C-T is described in Lovd as [Pathogenic].
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.64). . Strength limited to SUPPORTING due to the PP5.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PAH | NM_000277.3 | c.1199+17G>A | intron_variant | ENST00000553106.6 | NP_000268.1 | |||
PAH | NM_001354304.2 | c.1199+17G>A | intron_variant | NP_001341233.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PAH | ENST00000553106.6 | c.1199+17G>A | intron_variant | 1 | NM_000277.3 | ENSP00000448059 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00000658 AC: 1AN: 151910Hom.: 0 Cov.: 31
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GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461242Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1AN XY: 726920
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GnomAD4 genome AF: 0.00000658 AC: 1AN: 151910Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 74180
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:7Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Phenylketonuria Pathogenic:4
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Apr 17, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | May 01, 2023 | For these reasons, this variant has been classified as Pathogenic. Studies have shown that this variant is associated with altered splicing resulting in skipping of exon 11 (PMID: 29684050). ClinVar contains an entry for this variant (Variation ID: 102555). This variant is also known as IVS11+17G>A. This variant has been observed in individual(s) with hyperphenylalaninemia (PMID: 11139255, 30829006; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 11 of the PAH gene. It does not directly change the encoded amino acid sequence of the PAH protein. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Unidade de Bioquimica Genetica, Centro Hospitalar do Porto | Nov 10, 2017 | The variant was observed in four patients, two with a diagnosis of phenylketonuria (PKU) and the other two with a diagnosis of mild hyperphenylalaninemia (MHP). In the two PKU patients, the variant was found in compound heterozygosity with IVS10-11G>A (c.1066-11G>A), in intron 10, and c.250G>T (p.D84Y), in exon 3. Meanwhile, in the two MHP patients, it was found with IVS2+5G>C (c.168+5G>C), in intron 2, and c.754C>T (p.R252W), in exon 7. In silico analysis in Human Splicing Finder showed that it activates an intronic cryptic acceptor site, which potentially alters splicing. - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 11, 2024 | - - |
not provided Pathogenic:3Other:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 19, 2023 | Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 11139255, 31589614, 32668217, 30829006, 29684050) - |
not provided, no classification provided | literature only | DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE | - | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Apr 29, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Mar 01, 2024 | PAH: PM3:Very Strong, PM2, PS3:Supporting - |
Computational scores
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BayesDel_noAF
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at