rs1057516679
Variant summary
Our verdict is Pathogenic. Variant got 22 ACMG points: 22P and 0B. PVS1PM2PP3_StrongPP5_Very_Strong
The NM_000137.4(FAH):c.455G>A(p.Trp152Ter) variant causes a stop gained, splice region 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. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000137.4 stop_gained, splice_region
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 |
---|---|---|---|---|---|---|---|
FAH | NM_000137.4 | c.455G>A | p.Trp152Ter | stop_gained, splice_region_variant | 5/14 | ENST00000561421.6 | |
FAH | NM_001374377.1 | c.455G>A | p.Trp152Ter | stop_gained, splice_region_variant | 6/15 | ||
FAH | NM_001374380.1 | c.455G>A | p.Trp152Ter | stop_gained, splice_region_variant | 6/15 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FAH | ENST00000561421.6 | c.455G>A | p.Trp152Ter | stop_gained, splice_region_variant | 5/14 | 1 | NM_000137.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome Cov.: 30
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Tyrosinemia type I Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Mar 31, 2021 | For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has been observed in individual(s) with tyrosinemia type I (PMID: 23927806, 31030436, 30414057, 23225041). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 370677). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Trp152*) in the FAH gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in FAH are known to be pathogenic (PMID: 9101289, 9633815). - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Mar 22, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jul 19, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at