chr15-80180184-C-T
Variant names:
Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2
The NM_000137.4(FAH):c.1021C>T(p.Arg341Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0188 in 1,609,844 control chromosomes in the GnomAD database, including 357 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign,other (★★).
Frequency
Genomes: 𝑓 0.016 ( 26 hom., cov: 32)
Exomes 𝑓: 0.019 ( 331 hom. )
Consequence
FAH
NM_000137.4 missense
NM_000137.4 missense
Scores
7
5
6
Clinical Significance
Conservation
PhyloP100: 1.51
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 -20 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.02159214).
BP6
Variant 15-80180184-C-T is Benign according to our data. Variant chr15-80180184-C-T is described in ClinVar as [Likely_benign, other]. Clinvar id is 11868.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-80180184-C-T is described in Lovd as [Likely_benign]. Variant chr15-80180184-C-T is described in Lovd as [Benign].
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0157 (2383/152266) while in subpopulation NFE AF= 0.0236 (1608/68002). AF 95% confidence interval is 0.0227. There are 26 homozygotes in gnomad4. There are 1143 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 26 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
FAH | NM_000137.4 | c.1021C>T | p.Arg341Trp | missense_variant | Exon 12 of 14 | ENST00000561421.6 | NP_000128.1 | |
FAH | NM_001374377.1 | c.1021C>T | p.Arg341Trp | missense_variant | Exon 13 of 15 | NP_001361306.1 | ||
FAH | NM_001374380.1 | c.1021C>T | p.Arg341Trp | missense_variant | Exon 13 of 15 | NP_001361309.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0157 AC: 2385AN: 152148Hom.: 26 Cov.: 32
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GnomAD3 exomes AF: 0.0166 AC: 4096AN: 247378Hom.: 35 AF XY: 0.0162 AC XY: 2175AN XY: 134200
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GnomAD4 exome AF: 0.0192 AC: 27949AN: 1457578Hom.: 331 Cov.: 32 AF XY: 0.0190 AC XY: 13773AN XY: 725322
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GnomAD4 genome AF: 0.0157 AC: 2383AN: 152266Hom.: 26 Cov.: 32 AF XY: 0.0154 AC XY: 1143AN XY: 74458
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ClinVar
Significance: Benign/Likely benign; other
Submissions summary: Pathogenic:1Benign:9Other:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Benign:5Other:1
Likely benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
other, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jul 30, 2018 | - Variant classified as "other reportable" ??? variant is clinically benign (not associated with disease) but is reported when observed (e.g. pseudodeficiency alleles). |
Benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Feb 01, 2025 | FAH: BS1, BS2 - |
Likely benign, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Likely benign, criteria provided, single submitter | not provided | Breakthrough Genomics, Breakthrough Genomics | - | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Jan 04, 2018 | This variant is associated with the following publications: (PMID: 29326876, 27153395, 27535533, 25087612, 25333069, 21228398, 7977370, 11278491) - |
Tyrosinemia type I Benign:3Other:2
not provided, no classification provided | literature only | GeneReviews | - | A single pseudodeficiency allele, c.1021C>T (p.Arg341Trp), leads to decreased FAH enzyme activity and very little immunoreactive protein, but adequate amounts of FAH mRNA [Rootwelt et al 1994]. - |
Benign, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
other, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 26, 2018 | - pseudodeficiency allele |
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
Likely benign, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | May 18, 2021 | - - |
Fumarylacetoacetase pseudodeficiency Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 01, 1994 | - - |
not specified Benign:1
Benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Pathogenic
D;D;D
Eigen
Uncertain
Eigen_PC
Benign
FATHMM_MKL
Benign
D
LIST_S2
Pathogenic
.;.;D
MetaRNN
Benign
T;T;T
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
H;H;H
PrimateAI
Benign
T
PROVEAN
Pathogenic
D;D;D
REVEL
Pathogenic
Sift
Uncertain
D;D;D
Sift4G
Pathogenic
D;D;D
Polyphen
D;D;D
Vest4
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at