rs750741137
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000137.4(FAH):c.744del(p.Pro249HisfsTer55) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,890 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000048 ( 0 hom. )
Consequence
FAH
NM_000137.4 frameshift
NM_000137.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 9.24
Genes affected
FAH (HGNC:3579): (fumarylacetoacetate hydrolase) Predicted to enable fumarylacetoacetase activity. Predicted to be involved in L-phenylalanine catabolic process; homogentisate catabolic process; and tyrosine catabolic process. Predicted to act upstream of or within arginine catabolic process. Located in extracellular exosome. Implicated in tyrosinemia type I. [provided by Alliance of Genome Resources, Apr 2022]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 15-80173048-CG-C is Pathogenic according to our data. Variant chr15-80173048-CG-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 370275.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FAH | NM_000137.4 | c.744del | p.Pro249HisfsTer55 | frameshift_variant | 9/14 | ENST00000561421.6 | |
FAH | NM_001374377.1 | c.744del | p.Pro249HisfsTer55 | frameshift_variant | 10/15 | ||
FAH | NM_001374380.1 | c.744del | p.Pro249HisfsTer55 | frameshift_variant | 10/15 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FAH | ENST00000561421.6 | c.744del | p.Pro249HisfsTer55 | frameshift_variant | 9/14 | 1 | NM_000137.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
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GnomAD3 exomes AF: 0.00000795 AC: 2AN: 251488Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135916
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GnomAD4 exome AF: 0.00000479 AC: 7AN: 1461890Hom.: 0 Cov.: 32 AF XY: 0.00000825 AC XY: 6AN XY: 727248
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GnomAD4 genome ? Cov.: 33
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Tyrosinemia type I Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 04, 2024 | This sequence change creates a premature translational stop signal (p.Pro249Hisfs*55) 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). This variant is present in population databases (rs750741137, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with clinical features of tyrosinemia (PMID: 22554029). ClinVar contains an entry for this variant (Variation ID: 370275). For these reasons, this variant has been classified as Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Jan 05, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Aug 10, 2023 | - - |
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at