rs1057517084
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000137.4(FAH):βc.615delβ(p.Phe205LeufsTer2) variant causes a frameshift, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,460,500 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (β β ). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000137.4 frameshift, splice_region
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.615del | p.Phe205LeufsTer2 | frameshift_variant, splice_region_variant | 8/14 | ENST00000561421.6 | |
FAH | NM_001374377.1 | c.615del | p.Phe205LeufsTer2 | frameshift_variant, splice_region_variant | 9/15 | ||
FAH | NM_001374380.1 | c.615del | p.Phe205LeufsTer2 | frameshift_variant, splice_region_variant | 9/15 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FAH | ENST00000561421.6 | c.615del | p.Phe205LeufsTer2 | frameshift_variant, splice_region_variant | 8/14 | 1 | NM_000137.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1460500Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2AN XY: 726686
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Tyrosinemia type I Pathogenic:3
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Jul 26, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Mar 20, 2023 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 371201). This premature translational stop signal has been observed in individual(s) with tyrosinemia type 1 (PMID: 22554029). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Phe205Leufs*2) 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). - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jul 22, 2021 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at