rs786204683
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1_ModeratePM2PP3_StrongPP5_Very_Strong
The NM_000137.4(FAH):c.192+1G>T variant causes a splice donor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000117 in 1,451,764 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_000137.4 splice_donor
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FAH | NM_000137.4 | c.192+1G>T | splice_donor_variant | ENST00000561421.6 | |||
FAH | NM_001374377.1 | c.192+1G>T | splice_donor_variant | ||||
FAH | NM_001374380.1 | c.192+1G>T | splice_donor_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FAH | ENST00000561421.6 | c.192+1G>T | splice_donor_variant | 1 | NM_000137.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 0.0000117 AC: 17AN: 1451764Hom.: 0 Cov.: 29 AF XY: 0.00000968 AC XY: 7AN XY: 722894
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Tyrosinemia type I Pathogenic:5
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | - | - - |
Likely pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | May 13, 2021 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 24, 2020 | Variant summary: FAH c.192+1G>T is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes the canonical 5' splicing donor site. One predict the variant weakens the canonical 5' donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251492 control chromosomes. c.192+1G>T has been reported as part of a compound heterozygous genotype in the literature in at-least one individual affected with Tyrosinemia Type 1 (example, Bergman_1998). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No other 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 likely pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Nov 01, 2021 | NM_000137.2(FAH):c.192+1G>T is a canonical splice variant classified as likely pathogenic in the context of tyrosinemia type I. c.192+1G>T has been observed in cases with relevant disease (PMID: 9633815). Functional assessments of this variant are not available in the literature. Internal structural analysis of the variant is supportive of pathogenicity. c.192+1G>T has not been observed in population frequency databases. In summary, NM_000137.2(FAH):c.192+1G>T is a canonical splice variant that has internal structural support for pathogenicity and has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Mar 22, 2023 | For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 189085). Disruption of this splice site has been observed in individual(s) with tyrosinemia type I (PMID: 9633815). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 2 of the FAH gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in FAH are known to be pathogenic (PMID: 9101289, 9633815). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at