rs778387055
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_000137.4(FAH):c.497T>G(p.Val166Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,888 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 Likely pathogenic (★★).
Frequency
Consequence
NM_000137.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
FAH | NM_000137.4 | c.497T>G | p.Val166Gly | missense_variant | Exon 6 of 14 | ENST00000561421.6 | NP_000128.1 | |
FAH | NM_001374377.1 | c.497T>G | p.Val166Gly | missense_variant | Exon 7 of 15 | NP_001361306.1 | ||
FAH | NM_001374380.1 | c.497T>G | p.Val166Gly | missense_variant | Exon 7 of 15 | NP_001361309.1 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251476Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135908
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461888Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 727246
GnomAD4 genome Cov.: 31
ClinVar
Submissions by phenotype
Tyrosinemia type I Pathogenic:4
Variant summary: FAH c.497T>G (p.Val166Gly) results in a non-conservative amino acid change located in the Fumarylacetoacetase-like, C-terminal domain (IPR011234) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251476 control chromosomes. c.497T>G has been reported in the literature in individuals affected with Tyrosinemia Type 1 (examples: Bergman_1998, Rootwelt_1996, Dursun_2011). These data indicate that the variant is likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 23430822, 31300554, 8829657, 9633815). ClinVar contains an entry for this variant (Variation ID: 558415). Based on the evidence outlined above, the variant was classified as likely pathogenic. -
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In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies have shown that this variant affects FAH protein function (PMID: 31300554). This sequence change replaces valine with glycine at codon 166 of the FAH protein (p.Val166Gly). The valine residue is moderately conserved and there is a moderate physicochemical difference between valine and glycine. This variant is present in population databases (rs778387055, ExAC 0.001%). This variant has been observed in individual(s) with clinical features of tyrosinemia type 1 (PMID: 8318997, 8829657, 9633815, 23430822, 30414057). ClinVar contains an entry for this variant (Variation ID: 558415). -
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at