rs62514907
Variant summary
Our verdict is Pathogenic. Variant got 22 ACMG points: 22P and 0B. PVS1PM2PP3_StrongPP5_Very_Strong
The NM_000277.3(PAH):c.442-1G>C variant causes a splice acceptor change. The variant was absent in control chromosomes in GnomAD project. 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
Genomes: not found (cov: 32)
Consequence
PAH
NM_000277.3 splice_acceptor
NM_000277.3 splice_acceptor
Scores
5
1
1
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 5.24
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 22 ACMG points.
PVS1
?
Splicing variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 7.5, offset of 10, new splice context is: tttctcctacggttttaaAGatc. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
?
Variant 12-102866664-C-G is Pathogenic according to our data. Variant chr12-102866664-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 1065375.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr12-102866664-C-G is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PAH | NM_000277.3 | c.442-1G>C | splice_acceptor_variant | ENST00000553106.6 | |||
LOC124902999 | XR_007063428.1 | n.807+1437C>G | intron_variant, non_coding_transcript_variant | ||||
PAH | NM_001354304.2 | c.442-1G>C | splice_acceptor_variant | ||||
PAH | XM_017019370.2 | c.442-1G>C | splice_acceptor_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PAH | ENST00000553106.6 | c.442-1G>C | splice_acceptor_variant | 1 | NM_000277.3 | P1 | |||
PAH | ENST00000549111.5 | n.538-1G>C | splice_acceptor_variant, non_coding_transcript_variant | 1 | |||||
PAH | ENST00000307000.7 | c.427-1G>C | splice_acceptor_variant | 5 | |||||
PAH | ENST00000551988.5 | n.530+10798G>C | intron_variant, non_coding_transcript_variant | 3 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 30
GnomAD4 exome
Cov.:
30
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Phenylketonuria Pathogenic:1
Pathogenic, reviewed by expert panel | curation | ClinGen PAH Variant Curation Expert Panel | Dec 07, 2020 | This c.442-1G>C variant in PAH was reported in trans with pathogenic variant p.Val388Met in 1 Han Chinese patient with PAH deficiency (PMID: 28982351). This variant is absent from population databases gnomAD, 1000 Genomes and ESP. This variant in the -1 splice acceptor site of intron 4 disrupts the reading frame and is predicted to undergo nonsense mediated decay (NMD). The exon is present in biologically-relevant transcripts. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PM3, PP4. - |
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
D;D
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AG_spliceai
Position offset: -11
DS_AL_spliceai
Position offset: -1
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
No publications associated with this variant yet.