chr12-102917009-G-A
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Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BA1BP7
This summary comes from the ClinGen Evidence Repository: The c.60+62C>T intronic variant in PAH has a MAF of 0.3441 in gnomAD with 2,014 homozygotes.In summary, this variant meets criteria to be classified as benign for PAH. PAH-specific ACMG/AMP criteria applied: BA1, BS2, BP7. LINK:https://erepo.genome.network/evrepo/ui/classification/CA13630270/MONDO:0009861/006
Frequency
Genomes: 𝑓 0.37 ( 11390 hom., cov: 33)
Exomes 𝑓: 0.32 ( 69576 hom. )
Consequence
PAH
NM_000277.3 intron
NM_000277.3 intron
Scores
2
Clinical Significance
Conservation
PhyloP100: -0.508
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 Benign. Variant got -9 ACMG points.
BP7
BA1
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PAH | NM_000277.3 | c.60+62C>T | intron_variant | ENST00000553106.6 | |||
PAH | NM_001354304.2 | c.60+62C>T | intron_variant | ||||
PAH | XM_017019370.2 | c.60+62C>T | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PAH | ENST00000553106.6 | c.60+62C>T | intron_variant | 1 | NM_000277.3 | P1 |
Frequencies
GnomAD3 genomes AF: 0.372 AC: 56513AN: 151900Hom.: 11360 Cov.: 33
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GnomAD4 exome AF: 0.320 AC: 416270AN: 1299882Hom.: 69576 AF XY: 0.318 AC XY: 208511AN XY: 655128
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GnomAD4 genome AF: 0.372 AC: 56582AN: 152018Hom.: 11390 Cov.: 33 AF XY: 0.369 AC XY: 27407AN XY: 74308
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ClinVar
Significance: Benign
Submissions summary: Pathogenic:1Benign:9
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Phenylketonuria Pathogenic:1Benign:4
Likely pathogenic, no assertion criteria provided | case-control | Clinical Laboratory, Xuzhou Maternity and Child Health Care Hospital | Jun 26, 2018 | - - |
Benign, reviewed by expert panel | curation | ClinGen PAH Variant Curation Expert Panel | Nov 08, 2019 | The c.60+62C>T intronic variant in PAH has a MAF of 0.3441 in gnomAD with 2,014 homozygotes.In summary, this variant meets criteria to be classified as benign for PAH. PAH-specific ACMG/AMP criteria applied: BA1, BS2, BP7. - |
Benign, no assertion criteria provided | curation | Reproductive Health Research and Development, BGI Genomics | Jan 06, 2020 | NG_008690.2(NM_000277.2):c.60+62C>T in the gene PAH has an allele frequency of 0.496 in African subpopulation in the gnomAD database. A total of 2014 homozygous occurrences are observed in the gnomAD database. This evidence suggests the variant to be classified as benign. ACMG/AMP criteria applied: BA1, BS2. - |
Benign, criteria provided, single submitter | clinical testing | Pars Genome Lab | Jul 01, 2021 | - - |
Benign, criteria provided, single submitter | clinical testing | Molecular Genetics, Royal Melbourne Hospital | May 04, 2023 | African/African American population allele frequency is 48.34% (rs1522296, 4299/8672 alleles, 1055 homozygotes in gnomAD v2.1). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.2.1, this variant is classified as BENIGN. Following criteria are met: BA1 - |
not specified Benign:3
Benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Benign, criteria provided, single submitter | research | H3Africa Consortium | Oct 28, 2020 | While the frequency of the alternate allele in gnoMAD v2.0.2 is 0.521, its frequency in African populations is >5%. This suggests that previous classifications of this variant as pathogenic are in error. - |
PAH-related disorder Benign:1
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Feb 18, 2021 | This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
not provided Benign:1
Benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 03, 2015 | - - |
Computational scores
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Name
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
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