rs786204551
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Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The NM_000137.4(FAH):βc.1190delβ(p.Gln397ArgfsTer65) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000131 in 152,218 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (β β ).
Frequency
Genomes: π 0.000013 ( 0 hom., cov: 32)
Consequence
FAH
NM_000137.4 frameshift
NM_000137.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 5.77
Genes affected
FAH (HGNC:3579): (fumarylacetoacetate hydrolase) Predicted to enable fumarylacetoacetase activity. Predicted to be involved in L-phenylalanine catabolic process; homogentisate catabolic process; and tyrosine catabolic process. Predicted to act upstream of or within arginine catabolic process. Located in extracellular exosome. Implicated in tyrosinemia type I. [provided by Alliance of Genome Resources, Apr 2022]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 14 ACMG points.
PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 10 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 15-80186138-CA-C is Pathogenic according to our data. Variant chr15-80186138-CA-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 188907.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FAH | NM_000137.4 | c.1190del | p.Gln397ArgfsTer65 | frameshift_variant | 14/14 | ENST00000561421.6 | |
FAH | NM_001374377.1 | c.1190del | p.Gln397ArgfsTer65 | frameshift_variant | 15/15 | ||
FAH | NM_001374380.1 | c.1190del | p.Gln397ArgfsTer65 | frameshift_variant | 15/15 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FAH | ENST00000561421.6 | c.1190del | p.Gln397ArgfsTer65 | frameshift_variant | 14/14 | 1 | NM_000137.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152218Hom.: 0 Cov.: 32
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GnomAD4 exome Cov.: 31
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GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152218Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74360
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ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Tyrosinemia type I Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jun 09, 2023 | - - |
Likely pathogenic, criteria provided, single submitter | literature only | Counsyl | Jul 31, 2014 | - - |
Computational scores
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at