rs372637021
Variant summary
Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBP6_StrongBS2
The NM_000277.3(PAH):c.*19G>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00129 in 1,607,698 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★★).
Frequency
Genomes: 𝑓 0.0013 ( 1 hom., cov: 33)
Exomes 𝑓: 0.0013 ( 14 hom. )
Consequence
PAH
NM_000277.3 3_prime_UTR
NM_000277.3 3_prime_UTR
Scores
2
Clinical Significance
Conservation
PhyloP100: -0.654
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 -12 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.86).
BP6
?
Variant 12-102839156-C-A is Benign according to our data. Variant chr12-102839156-C-A is described in ClinVar as [Uncertain_significance]. Clinvar id is 255733.Status of the report is reviewed_by_expert_panel, 3 stars. We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=3, Benign=1}.
BS2
?
High Homozygotes in GnomAdExome at 8 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PAH | NM_000277.3 | c.*19G>T | 3_prime_UTR_variant | 13/13 | ENST00000553106.6 | ||
PAH | NM_001354304.2 | c.*19G>T | 3_prime_UTR_variant | 14/14 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PAH | ENST00000553106.6 | c.*19G>T | 3_prime_UTR_variant | 13/13 | 1 | NM_000277.3 | P1 | ||
PAH | ENST00000307000.7 | c.*19G>T | 3_prime_UTR_variant | 14/14 | 5 | ||||
PAH | ENST00000551114.2 | n.1040G>T | non_coding_transcript_exon_variant | 6/6 | 2 | ||||
PAH | ENST00000635528.1 | n.893G>T | non_coding_transcript_exon_variant | 5/5 | 3 |
Frequencies
GnomAD3 genomes ? AF: 0.00127 AC: 194AN: 152212Hom.: 1 Cov.: 33
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GnomAD3 exomes AF: 0.00219 AC: 550AN: 250934Hom.: 8 AF XY: 0.00271 AC XY: 367AN XY: 135640
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GnomAD4 exome AF: 0.00129 AC: 1882AN: 1455368Hom.: 14 Cov.: 29 AF XY: 0.00157 AC XY: 1140AN XY: 724392
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:3Benign:5
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Phenylketonuria Uncertain:3Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Apr 27, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | May 18, 2021 | - - |
Uncertain significance, reviewed by expert panel | curation | ClinGen PAH Variant Curation Expert Panel | Sep 27, 2019 | The c.*19G>T variant in PAH has been reported in a 2 patients with PKU (PP4; PMID: 12765842, 26210745) This variant has an allele frequency greater than expected: gnomAD MAF=0.00812 (>0.002) and 8 homozygotes (BS1). Computational evidence is conflicting (TraP score: 0.085; HSF: activation of an exonic cryptic donor site; MaxENT 3' Motif:+1145.71). In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PP4, BS1. - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Sep 21, 2023 | - - |
not specified Benign:4
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 25, 2023 | Variant summary: PAH c.*19G>T is located in the untranslated mRNA region downstream of the termination codon. The variant allele was found at a frequency of 0.0022 in 252634 control chromosomes (gnomAD, da Silva_2003, Alibakhshi_2022), predominantly at a frequency of 0.0081 within the South Asian subpopulation in the gnomAD database, including 4 homozygotes. This frequency is slightly higher than expected for a pathogenic variant in PAH causing Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (0.0081 vs 0.0079), suggesting this variant is likely a benign polymorphism found primarily in South Asians. The variant has been reported in the literature in individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (da Silva_2003, Trunzo_2015). However, co-occurrence with another pathogenic variant (in cis) has been reported (PAH c.1223G>A, p.R408Q), providing supporting evidence for a benign role (Trunzo_2015). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submitters have assessed the variant since 2014: three submitters (including one expert panel) classified the variant as uncertain significance, two as likely benign, and one as benign. Based on the evidence outlined above, the variant was classified as likely benign. - |
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jul 17, 2017 | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Aug 17, 2017 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
Computational scores
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Name
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BayesDel_noAF
Benign
Cadd
Benign
Dann
Benign
RBP_binding_hub_radar
RBP_regulation_power_radar
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