chr12-102855224-G-T
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000277.3(PAH):c.618C>A(p.Tyr206Ter) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 33)
Consequence
PAH
NM_000277.3 stop_gained
NM_000277.3 stop_gained
Scores
5
1
1
Clinical Significance
Conservation
PhyloP100: 5.94
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 undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 12-102855224-G-T is Pathogenic according to our data. Variant chr12-102855224-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 556660.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr12-102855224-G-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PAH | NM_000277.3 | c.618C>A | p.Tyr206Ter | stop_gained | 6/13 | ENST00000553106.6 | |
PAH | NM_001354304.2 | c.618C>A | p.Tyr206Ter | stop_gained | 7/14 | ||
PAH | XM_017019370.2 | c.618C>A | p.Tyr206Ter | stop_gained | 6/7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PAH | ENST00000553106.6 | c.618C>A | p.Tyr206Ter | stop_gained | 6/13 | 1 | NM_000277.3 | P1 | |
PAH | ENST00000549111.5 | n.714C>A | non_coding_transcript_exon_variant | 6/6 | 1 | ||||
PAH | ENST00000307000.7 | c.603C>A | p.Tyr201Ter | stop_gained | 7/14 | 5 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251330Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135818
GnomAD3 exomes
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251330
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135818
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GnomAD4 exome Cov.: 34
GnomAD4 exome
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34
GnomAD4 genome ? Cov.: 33
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33
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:6
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Phenylketonuria Pathogenic:6
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Sep 14, 2023 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 08, 2017 | Variant summary: The PAH c.618C>A (p.Tyr206X) variant results in a premature termination codon, predicted to cause a truncated or absent PAH 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 (e.g. c.727C>T, p.Arg243X; c.1055delG, p.Gly352fsX48; c.1089delG, p.Lys363fsX37). One in silico tool predicts a damaging outcome for this variant. One functional study confirmed that the variant leads to a nonsense mutation that caused significant reduction in mutant transcript levels possibly through activation of nonsense mediated decay (Bashyam 2014). This variant was found in 1/121330 control chromosomes at a frequency of 0.00082%, which does not exceed the estimated maximal expected allele frequency of a pathogenic PAH variant (0.79057%). The variant was reported in the literature in multiple patients with PKU (Song 2006, Bashyam 2014, Li 2015, Acosta 2001). Taken together, this variant is classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Feb 13, 2018 | - - |
Pathogenic, reviewed by expert panel | curation | ClinGen PAH Variant Curation Expert Panel | Oct 13, 2023 | The c.618C>A (p.Tyr206Ter) is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 6/13 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. It has been detected in 4 patients with classic PKU with known pathogenic variants: c.611A>G (PMID: 16256386); p.Arg241Cys (PMID:25456745); and c.1197A>T p.Val399Val (PMID: 30050108). This variant has extremely low frequency in gnomAD (MAF=0.00005). In summary, this variant meets criteria to be classified as Pathogenic for PAH deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen PAH VCEP: PM2_supporting, PM3_strong, PP4, PVS1. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 22, 2023 | This sequence change creates a premature translational stop signal (p.Tyr206*) 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 (rs62517201, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with phenylketonuria (PMID: 16256386, 24130151, 27121329). ClinVar contains an entry for this variant (Variation ID: 556660). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
A;A
Vest4
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at