15-80181048-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.1069G>T(p.Glu357*) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000856 in 1,612,660 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
Consequence
NM_000137.4 stop_gained
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 rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
FAH | NM_000137.4 | c.1069G>T | p.Glu357* | stop_gained | Exon 13 of 14 | ENST00000561421.6 | NP_000128.1 | |
FAH | NM_001374377.1 | c.1069G>T | p.Glu357* | stop_gained | Exon 14 of 15 | NP_001361306.1 | ||
FAH | NM_001374380.1 | c.1069G>T | p.Glu357* | stop_gained | Exon 14 of 15 | NP_001361309.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000788 AC: 12AN: 152224Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000278 AC: 7AN: 251462Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135906
GnomAD4 exome AF: 0.0000863 AC: 126AN: 1460436Hom.: 0 Cov.: 30 AF XY: 0.0000812 AC XY: 59AN XY: 726608
GnomAD4 genome AF: 0.0000788 AC: 12AN: 152224Hom.: 0 Cov.: 32 AF XY: 0.0000672 AC XY: 5AN XY: 74352
ClinVar
Submissions by phenotype
Tyrosinemia type I Pathogenic:7
NM_000137.2(FAH):c.1069G>T(E357*) is classified as pathogenic in the context of tyrosinemia type I. Sources cited for classification include the following: PMID 8028615, 7929843, 7757089, 8076937, 15638932, 8557261 and 8318997. Classification of NM_000137.2(FAH):c.1069G>T(E357*) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening. -
Variant summary: The FAH c.1069G>T (p.Glu357X) variant results in a premature termination codon, predicted to cause a truncated or absent FAH protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One in silico tool predicts a damaging outcome for this variant. This variant was found in 3/121286 control chromosomes at a frequency of 0.0000247, which does not exceed the estimated maximal expected allele frequency of a pathogenic FAH variant (0.0025). The variant has been reported in numerous affected indiivduals in the literature. In addition, one databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -
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This sequence change creates a premature translational stop signal (p.Glu357*) 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 (rs121965075, gnomAD 0.006%). 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: 11871). For these reasons, this variant has been classified as Pathogenic. -
The p.Glu357X variant in FAH has been reported in at least two compound heterozy gous individuals with Tyrosinemia type 1 (Grompe 1993, Kvittingen 1994, Ploos va n Amstel 1996). Sequencing of a patient mRNA showed a loss of expression of the transcript with this variant (Ploos van Amstel 1996). This variant has been iden tified in 9/129178 European chromosomes by the Genome Aggregation Database (gnom AD, http://gnomad.broadinstitute.org) and reported in ClinVar (Variation ID: 118 71). This nonsense variant leads to a premature termination codon at position 35 7, which is predicted to lead to a truncated or absent protein. Biallelic loss o f function of the FAH gene is an established disease mechanism in Tyrosinemia Ty pe 1. In summary, this variant meets criteria to be classified as pathogenic for Tyrosinemia Type 1 in an autosomal recessive manner based upon presence in affe cted individuals, low frequency in controls, and the predicted impact to the pro tein. ACMG/AMP criteria applied: PVS1, PM3_Strong, PM2, PS3_Supporting. -
not provided Pathogenic:1
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: 9633815, 8318997, 8557261, 7929843, 15638932, 22975760, 25525159, 7757089, 26689913, 27415407, 22554029, 29625052, 8076937) -
FAH-related disorder Pathogenic:1
The FAH c.1069G>T variant is predicted to result in premature protein termination (p.Glu357*). This variant has been commonly reported as causative for tyrosinemia type I (Grompe et al. 1993. PubMed ID: 8318997; Angileri et al. 2015. PubMed ID: 25681080). This variant is reported in 0.0070% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/15-80473390-G-T). Nonsense variants in FAH are expected to be pathogenic. This variant is interpreted as pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at