12-102852814-C-T
Variant summary
Our verdict is Pathogenic. Variant got 22 ACMG points: 22P and 0B. PVS1PM2PP3_StrongPP5_Very_Strong
The NM_000277.3(PAH):c.842+1G>A variant causes a splice donor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000582 in 1,613,868 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★★).
Frequency
Consequence
NM_000277.3 splice_donor
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 22 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PAH | NM_000277.3 | c.842+1G>A | splice_donor_variant | ENST00000553106.6 | |||
PAH | NM_001354304.2 | c.842+1G>A | splice_donor_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PAH | ENST00000553106.6 | c.842+1G>A | splice_donor_variant | 1 | NM_000277.3 | P1 | |||
PAH | ENST00000307000.7 | c.827+1G>A | splice_donor_variant | 5 | |||||
PAH | ENST00000635477.1 | c.3+1G>A | splice_donor_variant | 5 | |||||
PAH | ENST00000549247.6 | n.601+1G>A | splice_donor_variant, non_coding_transcript_variant | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000394 AC: 6AN: 152156Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000438 AC: 11AN: 251272Hom.: 0 AF XY: 0.0000442 AC XY: 6AN XY: 135802
GnomAD4 exome AF: 0.0000602 AC: 88AN: 1461712Hom.: 0 Cov.: 31 AF XY: 0.0000509 AC XY: 37AN XY: 727166
GnomAD4 genome ? AF: 0.0000394 AC: 6AN: 152156Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4AN XY: 74330
ClinVar
Submissions by phenotype
Phenylketonuria Pathogenic:11
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 14, 2020 | Variant summary: PAH c.842+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5 splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4.4e-05 in 251272 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in PAH causing Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (4.4e-05 vs 0.0079), allowing no conclusion about variant significance. c.842+1G>A has been reported in the literature in multiple individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria; Example: Dianzani_1991, Leuzzi_2006, Aldamiz-Echevarria_2016, Li_2018). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six other ClinVar submitters (evaluation after 2014) including an expert panel (ClinGen PAH Variant Curation Expert Panel) cite the variant as likely pathogenic/pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, reviewed by expert panel | curation | ClinGen PAH Variant Curation Expert Panel | Aug 13, 2018 | PAH-specific ACMG/AMP criteria applied: PVS1: Canonical +1 splice site; PM2: gnomAD MAF 0.00008; PP4: Reported in 3 PKU populations: Slovak, Germany, Italy (PMID:1671810; PMID:10394930; PMID:23764561); PM3: (PMID:20188615; PMID:24941924). In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PVS1, PM2, PP4, PM3). - |
Pathogenic, criteria provided, single submitter | clinical testing | Elsea Laboratory, Baylor College of Medicine | Apr 01, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 20, 2023 | This sequence change affects a donor splice site in intron 7 of the PAH gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in PAH are known to be pathogenic (PMID: 1301187, 9634518). This variant is present in population databases (rs5030852, gnomAD 0.008%). Disruption of this splice site has been observed in individual(s) with phenylketonuria (PMID: 16256386, 20188615, 23764561, 24941924). This variant is also known as IVS VII-1G>A and IVS7+1G>A. ClinVar contains an entry for this variant (Variation ID: 599). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Equipe Genetique des Anomalies du Developpement, Université de Bourgogne | Aug 16, 2017 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 01, 1991 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Nov 03, 2022 | The c.842+1G>A in PAH has been reported in at least 6 homozygous and over 50 compound heterozygous individuals affected with Hyperphenylalaninemia or Phenylketonuria (selected publications: Hillert 2020 PMID: 32668217). This variant was classified as Pathogenic on August 13, 2018 by the ClinGen-approved ClinGen PAH Variant Curation Expert Panel (Variation ID 599) and was identified in 5/68040 European and in 1/10608 Finnish chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant occurs within the canonical splice site (+/- 1,2) and is predicted to cause altered splicing leading to an abnormal or absent protein. Loss of function of the PAH gene is an established disease mechanism in autosomal recessive Phenylketonuria. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive hyperphenylalanemia/phenylkenonuria. ACMG/AMP Criteria applied: PM2_Supporting, PVS1, PM3_Very Strong. - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Sep 06, 2023 | - - |
Likely pathogenic, criteria provided, single submitter | literature only | Counsyl | Jan 16, 2015 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 24, 2023 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
not provided Pathogenic:4Other:1
not provided, no classification provided | literature only | DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 05, 2021 | Canonical splice site variant predicted to result in a null allele in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 32668217, 31589614, 30747360, 26666653, 25525159, 23764561, 20188615, 16256386, 24941924, 26589311, 20920871, 1671810, 17935162) - |
Pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Sep 01, 2019 | - - |
Likely pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at