rs60585303
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Variant summary
Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBA1
The NM_000137.4(FAH):c.1180+4A>G variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00834 in 1,597,466 control chromosomes in the GnomAD database, including 921 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).
Frequency
Genomes: 𝑓 0.042 ( 455 hom., cov: 32)
Exomes 𝑓: 0.0048 ( 466 hom. )
Consequence
FAH
NM_000137.4 splice_donor_region, intron
NM_000137.4 splice_donor_region, intron
Scores
2
Splicing: ADA: 0.8486
2
Clinical Significance
Conservation
PhyloP100: 0.731
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 Benign. Variant got -18 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.37).
BP6
?
Variant 15-80181163-A-G is Benign according to our data. Variant chr15-80181163-A-G is described in ClinVar as [Benign]. Clinvar id is 255278.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BA1
?
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.144 is higher than 0.05.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FAH | NM_000137.4 | c.1180+4A>G | splice_donor_region_variant, intron_variant | ENST00000561421.6 | |||
FAH | NM_001374377.1 | c.1180+4A>G | splice_donor_region_variant, intron_variant | ||||
FAH | NM_001374380.1 | c.1180+4A>G | splice_donor_region_variant, intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FAH | ENST00000561421.6 | c.1180+4A>G | splice_donor_region_variant, intron_variant | 1 | NM_000137.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0423 AC: 6436AN: 152138Hom.: 453 Cov.: 32
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GnomAD3 exomes AF: 0.0118 AC: 2975AN: 251354Hom.: 196 AF XY: 0.00856 AC XY: 1163AN XY: 135856
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GnomAD4 exome AF: 0.00475 AC: 6871AN: 1445210Hom.: 466 Cov.: 26 AF XY: 0.00411 AC XY: 2956AN XY: 719940
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GnomAD4 genome ? AF: 0.0424 AC: 6451AN: 152256Hom.: 455 Cov.: 32 AF XY: 0.0407 AC XY: 3030AN XY: 74444
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ClinVar
Significance: Benign
Submissions summary: Benign:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:2
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Jan 28, 2016 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
Tyrosinemia type I Benign:2
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
Computational scores
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Name
Calibrated prediction
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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dbscSNV1_ADA
Benign
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at