rs121965077
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_000137.4(FAH):āc.1141A>Gā(p.Arg381Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,616 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (ā ā ).
Frequency
Genomes: not found (cov: 32)
Exomes š: 6.8e-7 ( 0 hom. )
Consequence
FAH
NM_000137.4 missense
NM_000137.4 missense
Scores
12
4
3
Clinical Significance
Conservation
PhyloP100: 1.69
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 14 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.994
PP5
Variant 15-80181120-A-G is Pathogenic according to our data. Variant chr15-80181120-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 11872.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
FAH | NM_000137.4 | c.1141A>G | p.Arg381Gly | missense_variant | 13/14 | ENST00000561421.6 | NP_000128.1 | |
FAH | NM_001374377.1 | c.1141A>G | p.Arg381Gly | missense_variant | 14/15 | NP_001361306.1 | ||
FAH | NM_001374380.1 | c.1141A>G | p.Arg381Gly | missense_variant | 14/15 | NP_001361309.1 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461616Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 727102
GnomAD4 exome
AF:
AC:
1
AN:
1461616
Hom.:
Cov.:
31
AF XY:
AC XY:
1
AN XY:
727102
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Tyrosinemia type I Pathogenic:5
Pathogenic, no assertion criteria provided | literature only | OMIM | Feb 01, 1995 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jun 05, 2024 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 04, 2024 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 01, 2023 | This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 381 of the FAH protein (p.Arg381Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of tyrosinemia type 1 (PMID: 7757089; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 11872). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt FAH protein function. Experimental studies have shown that this missense change affects FAH function (PMID: 31300554). For these reasons, this variant has been classified as Pathogenic. - |
Likely pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | May 30, 2018 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Pathogenic
D;D;D
Eigen
Uncertain
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Pathogenic
.;.;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Uncertain
M;M;M
PrimateAI
Benign
T
PROVEAN
Pathogenic
D;D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D;D
Sift4G
Pathogenic
D;D;D
Polyphen
D;D;D
Vest4
MutPred
Loss of catalytic residue at R381 (P = 0.0327);Loss of catalytic residue at R381 (P = 0.0327);Loss of catalytic residue at R381 (P = 0.0327);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at