rs61747292
Variant summary
Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1
The NM_000277.3(PAH):c.963C>T(p.Leu321=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00277 in 1,613,290 control chromosomes in the GnomAD database, including 123 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).
Frequency
Genomes: 𝑓 0.014 ( 69 hom., cov: 32)
Exomes 𝑓: 0.0016 ( 54 hom. )
Consequence
PAH
NM_000277.3 synonymous
NM_000277.3 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -1.48
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 -21 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.79).
BP6
?
Variant 12-102846901-G-A is Benign according to our data. Variant chr12-102846901-G-A is described in ClinVar as [Benign]. Clinvar id is 102911.Status of the report is reviewed_by_expert_panel, 3 stars.
BP7
?
Synonymous conserved (PhyloP=-1.48 with no splicing effect.
BA1
?
GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.054 is higher than 0.05.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PAH | NM_000277.3 | c.963C>T | p.Leu321= | synonymous_variant | 9/13 | ENST00000553106.6 | |
PAH | NM_001354304.2 | c.963C>T | p.Leu321= | synonymous_variant | 10/14 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PAH | ENST00000553106.6 | c.963C>T | p.Leu321= | synonymous_variant | 9/13 | 1 | NM_000277.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0144 AC: 2185AN: 152092Hom.: 68 Cov.: 32
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GnomAD3 exomes AF: 0.00385 AC: 968AN: 251262Hom.: 26 AF XY: 0.00305 AC XY: 414AN XY: 135796
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GnomAD4 exome AF: 0.00156 AC: 2275AN: 1461080Hom.: 54 Cov.: 30 AF XY: 0.00134 AC XY: 973AN XY: 726900
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GnomAD4 genome ? AF: 0.0144 AC: 2198AN: 152210Hom.: 69 Cov.: 32 AF XY: 0.0140 AC XY: 1040AN XY: 74424
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ClinVar
Significance: Benign
Submissions summary: Benign:7Other:1
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Phenylketonuria Benign:4
Benign, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Benign, reviewed by expert panel | curation | ClinGen PAH Variant Curation Expert Panel | Jul 29, 2018 | PAH-specific ACMG/AMP criteria applied: BS1: >0.02% as set by the PAH specific specifications; BP7: ; BS3_Supporting: cDNA method demonstrates 98% and intinic system demonstrates 81% residual enzyme activity; BS2: 38 homozygotes in gnomAD. In summary this variant meets criteria to be classified as benign for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (BS1, BP7, BS3_Supporting, BS2). - |
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | - - |
not specified Benign:3
Benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Oct 12, 2016 | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Feb 27, 2018 | 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. - |
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 17, 2019 | Variant summary: PAH c.963C>T alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0039 in 251262 control chromosomes, predominantly at a frequency of 0.053 within the African or African-American subpopulation in the gnomAD database, including 26 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 7-folds higher than the estimated maximal expected allele frequency for a pathogenic variant in PAH causing Phenylalanine Hydroxylase Deficiency (Phenylketonuria) phenotype (0.0079), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. Three ClinVar submissions from clinical diagnostic laboratories and an expert panel (ClinGen)(evaluation after 2014) cite the variant as benign. Based on the evidence outlined above, the variant was classified as benign. - |
not provided Other:1
not provided, no classification provided | literature only | DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE | - | - - |
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