rs1297118863
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000137.4(FAH):c.1210G>A(p.Gly404Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000112 in 1,614,020 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G404R) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000137.4 missense
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/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FAH | NM_000137.4 | c.1210G>A | p.Gly404Ser | missense_variant | 14/14 | ENST00000561421.6 | |
FAH | NM_001374377.1 | c.1210G>A | p.Gly404Ser | missense_variant | 15/15 | ||
FAH | NM_001374380.1 | c.1210G>A | p.Gly404Ser | missense_variant | 15/15 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FAH | ENST00000561421.6 | c.1210G>A | p.Gly404Ser | missense_variant | 14/14 | 1 | NM_000137.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152174Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251442Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135892
GnomAD4 exome AF: 0.0000109 AC: 16AN: 1461846Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 8AN XY: 727222
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152174Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74316
ClinVar
Submissions by phenotype
Tyrosinemia type I Pathogenic:3
Likely pathogenic, criteria provided, single submitter | clinical testing | 3billion | Feb 23, 2023 | The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.001%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.97; 3Cnet: 0.51). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000459903). A different missense change at the same codon (p.Gly404Arg) has been reported to be associated with FAH -related disorder (ClinVar ID: VCV001348938). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Nov 14, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 25, 2024 | This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 404 of the FAH protein (p.Gly404Ser). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with tyrosinemia type I (PMID: 21117323, 27814443; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 459903). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt FAH protein function with a negative predictive value of 80%. This variant disrupts the p.Gly404 amino acid residue in FAH. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Feb 01, 2020 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at