chr15-80153055-A-C
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Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_000137.4(FAH):c.1A>C(p.Met1?) variant causes a start lost change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).
Frequency
Genomes: not found (cov: 33)
Consequence
FAH
NM_000137.4 start_lost
NM_000137.4 start_lost
Scores
5
6
5
Clinical Significance
Conservation
PhyloP100: 7.47
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 12 ACMG points.
PVS1
Start lost variant, no new inframe start found.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 15-80153055-A-C is Pathogenic according to our data. Variant chr15-80153055-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1066042.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
FAH | NM_000137.4 | c.1A>C | p.Met1? | start_lost | 1/14 | ENST00000561421.6 | NP_000128.1 | |
FAH | NM_001374377.1 | c.1A>C | p.Met1? | start_lost | 2/15 | NP_001361306.1 | ||
FAH | NM_001374380.1 | c.1A>C | p.Met1? | start_lost | 2/15 | NP_001361309.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
FAH | ENST00000561421.6 | c.1A>C | p.Met1? | start_lost | 1/14 | 1 | NM_000137.4 | ENSP00000453347 | P1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 genomes
Cov.:
33
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome Cov.: 33
GnomAD4 genome
Cov.:
33
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Tyrosinemia type I Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jul 09, 2020 | This variant has not been reported in the literature in individuals with FAH-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change affects the initiator methionine of the FAH mRNA. The next in-frame methionine is located at codon 71. A different variant (c.1A>G) giving rise to the same protein effect observed here (p.Met1?) has been determined to be pathogenic (PMID: 21764616, 22802474, 24016420). This suggests that this variant is also likely to be causative of disease. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Benign
DEOGEN2
Benign
T;T;T;T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;.;.;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D
MetaSVM
Uncertain
D
MutationTaster
Benign
D;D;D
PROVEAN
Benign
N;N;N;N
REVEL
Pathogenic
Sift
Uncertain
D;T;T;T
Sift4G
Benign
T;T;T;T
Polyphen
0.84
.;P;P;P
Vest4
0.95, 0.73, 0.91
MutPred
Loss of disorder (P = 0.1523);Loss of disorder (P = 0.1523);Loss of disorder (P = 0.1523);Loss of disorder (P = 0.1523);
MVP
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
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
Publications
No publications associated with this variant yet.