rs1429055740
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000277.3(PAH):c.1171_1172del(p.Ser391PhefsTer2) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000186 in 1,611,750 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.0000067 ( 0 hom., cov: 31)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
PAH
NM_000277.3 frameshift
NM_000277.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 6.13
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
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Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
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Very rare variant in population databases, with high coverage;
PP5
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Variant 12-102843672-ACT-A is Pathogenic according to our data. Variant chr12-102843672-ACT-A is described in ClinVar as [Pathogenic]. Clinvar id is 553594.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr12-102843672-ACT-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PAH | NM_000277.3 | c.1171_1172del | p.Ser391PhefsTer2 | frameshift_variant | 11/13 | ENST00000553106.6 | |
PAH | NM_001354304.2 | c.1171_1172del | p.Ser391PhefsTer2 | frameshift_variant | 12/14 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PAH | ENST00000553106.6 | c.1171_1172del | p.Ser391PhefsTer2 | frameshift_variant | 11/13 | 1 | NM_000277.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000666 AC: 1AN: 150106Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251290Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135796
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GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461644Hom.: 0 AF XY: 0.00000138 AC XY: 1AN XY: 727118
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GnomAD4 genome ? AF: 0.00000666 AC: 1AN: 150106Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 73168
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Phenylketonuria Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Aug 30, 2017 | - - |
Pathogenic, reviewed by expert panel | curation | ClinGen PAH Variant Curation Expert Panel | Jun 19, 2020 | The c.1171_1172del (p.Ser391PhefsTer2) variant in PAH has been reported in an individual with Classic PKU (BH4 deficiency excluded). (PMID: 8268925, 11708866, 27121329) in trans with pathogenic variant p.Ser349Pro. It is a frameshift variant in exon 11 of 13 in PAH, predicted to undergo nonsense mediated decay with the truncated region critical to protein function. This variant has an extremely low allele frequency (MAF=0.000008799) in gnomAD. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PM3, PP4_Moderate, - |
Computational scores
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Details are displayed if max score is > 0.2
DS_DL_spliceai
Position offset: -26
Find out detailed SpliceAI scores and Pangolin per-transcript scores at