rs121965077
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_000137.4(FAH):c.1141A>G(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 Pathogenic (★★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
FAH
NM_000137.4 missense
NM_000137.4 missense
Scores
11
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]
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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 [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 | UniProt |
---|---|---|---|---|---|---|---|
FAH | NM_000137.4 | c.1141A>G | p.Arg381Gly | missense_variant | 13/14 | ENST00000561421.6 | |
FAH | NM_001374377.1 | c.1141A>G | p.Arg381Gly | missense_variant | 14/15 | ||
FAH | NM_001374380.1 | c.1141A>G | p.Arg381Gly | missense_variant | 14/15 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FAH | ENST00000561421.6 | c.1141A>G | p.Arg381Gly | missense_variant | 13/14 | 1 | NM_000137.4 | P1 |
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
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GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Tyrosinemia type I Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jun 06, 2023 | - - |
Likely pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | May 30, 2018 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Feb 01, 1995 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 01, 2023 | This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects FAH function (PMID: 31300554). 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. ClinVar contains an entry for this variant (Variation ID: 11872). 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. 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). - |
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
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Uncertain
M;M;M
MutationTaster
Benign
A;A;A;A
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