chr12-102894893-A-T
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000277.3(PAH):c.194T>A(p.Ile65Asn) variant causes a missense change involving the alteration of a conserved nucleotide. 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 Likely pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I65T) has been classified as Pathogenic.
Frequency
Consequence
NM_000277.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PAH | NM_000277.3 | c.194T>A | p.Ile65Asn | missense_variant | 3/13 | ENST00000553106.6 | |
LOC124902999 | XR_007063428.1 | n.863-9805A>T | intron_variant, non_coding_transcript_variant | ||||
PAH | NM_001354304.2 | c.194T>A | p.Ile65Asn | missense_variant | 4/14 | ||
PAH | XM_017019370.2 | c.194T>A | p.Ile65Asn | missense_variant | 3/7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PAH | ENST00000553106.6 | c.194T>A | p.Ile65Asn | missense_variant | 3/13 | 1 | NM_000277.3 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 30
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Phenylketonuria Pathogenic:1
Likely pathogenic, reviewed by expert panel | curation | ClinGen PAH Variant Curation Expert Panel | Dec 09, 2018 | The c.194T>A (p.Ile65Asn) variant was identified in a patient with classic PKU. BH4 deficiency was ruled out. (PMID: 9521426). It was detected in trans with known pathogenic mutation c.143T>C (p.L48S). It has an extremely low frequency in PAGE (0.00026); and is absent from ExAC, 1000 Genomes, gnomAD. Multiple lines of computational evidence support a deleterious effect (SIFT, Polyphen-2, MutationTaster; REVEL=0.957). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3, PP4_Moderate, PP3. - |
not provided Other:1
not provided, no classification provided | literature only | DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at