rs121965077

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_000137.4(FAH):ā€‹c.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

Scores

12
4
3

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 1.69
Variant links:
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 [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
FAHNM_000137.4 linkc.1141A>G p.Arg381Gly missense_variant 13/14 ENST00000561421.6 NP_000128.1 P16930-1A0A384P5L6
FAHNM_001374377.1 linkc.1141A>G p.Arg381Gly missense_variant 14/15 NP_001361306.1
FAHNM_001374380.1 linkc.1141A>G p.Arg381Gly missense_variant 14/15 NP_001361309.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
FAHENST00000561421.6 linkc.1141A>G p.Arg381Gly missense_variant 13/141 NM_000137.4 ENSP00000453347.2 P16930-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461616
Hom.:
0
Cov.:
31
AF XY:
0.00000138
AC XY:
1
AN XY:
727102
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
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 providedliterature onlyOMIMFeb 01, 1995- -
Likely pathogenic, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsJun 05, 2024- -
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsFeb 04, 2024- -
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 01, 2023This 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 providedclinical testingNatera, Inc.May 30, 2018- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.91
BayesDel_addAF
Pathogenic
0.50
D
BayesDel_noAF
Pathogenic
0.49
CADD
Uncertain
24
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.94
D;D;D
Eigen
Uncertain
0.19
Eigen_PC
Benign
0.025
FATHMM_MKL
Uncertain
0.84
D
LIST_S2
Pathogenic
0.99
.;.;D
M_CAP
Pathogenic
0.83
D
MetaRNN
Pathogenic
0.99
D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Uncertain
2.8
M;M;M
PrimateAI
Benign
0.45
T
PROVEAN
Pathogenic
-6.5
D;D;D
REVEL
Pathogenic
0.91
Sift
Pathogenic
0.0
D;D;D
Sift4G
Pathogenic
0.0
D;D;D
Polyphen
1.0
D;D;D
Vest4
0.99
MutPred
0.90
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
0.95
MPC
0.95
ClinPred
1.0
D
GERP RS
0.91
Varity_R
0.97
gMVP
0.96

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs121965077; hg19: chr15-80473462; API