15-80181069-G-T
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000137.4(FAH):c.1090G>T(p.Glu364Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000905 in 1,613,620 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000098 ( 0 hom. )
Consequence
FAH
NM_000137.4 stop_gained
NM_000137.4 stop_gained
Scores
5
1
1
Clinical Significance
Conservation
PhyloP100: 8.87
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 15-80181069-G-T is Pathogenic according to our data. Variant chr15-80181069-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 11867.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-80181069-G-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FAH | NM_000137.4 | c.1090G>T | p.Glu364Ter | stop_gained | 13/14 | ENST00000561421.6 | |
FAH | NM_001374377.1 | c.1090G>T | p.Glu364Ter | stop_gained | 14/15 | ||
FAH | NM_001374380.1 | c.1090G>T | p.Glu364Ter | stop_gained | 14/15 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FAH | ENST00000561421.6 | c.1090G>T | p.Glu364Ter | stop_gained | 13/14 | 1 | NM_000137.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152184Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000239 AC: 6AN: 251474Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135914
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Tyrosinemia type I Pathogenic:5
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Feb 02, 2020 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 1993 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 02, 2020 | Variant summary: FAH c.1090G>T (p.Glu364X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 2.4e-05 in 251474 control chromosomes. c.1090G>T has been reported in the literature in individuals affected with Tyrosinemia Type 1 (Grompe_1994, Poudrier_1999). These data indicate that the variant is likely to be associated with disease. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 25, 2023 | This sequence change creates a premature translational stop signal (p.Glu364*) 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 (rs121965076, gnomAD 0.008%). This premature translational stop signal has been observed in individual(s) with tyrosinemia type I (PMID: 8318997). ClinVar contains an entry for this variant (Variation ID: 11867). For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 30, 2023 | Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25087612, 25525159, 29625052, 26689913, 10073910, 8318997) - |
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
A;A;A;A
Vest4
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at