14-74716091-A-G
Position:
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3
The NM_015962.5(FCF1):āc.284A>Gā(p.Tyr95Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,474 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 Uncertain significance (ā ).
Frequency
Genomes: not found (cov: 32)
Exomes š: 0.0000027 ( 0 hom. )
Consequence
FCF1
NM_015962.5 missense
NM_015962.5 missense
Scores
10
4
3
Clinical Significance
Conservation
PhyloP100: 9.04
Genes affected
FCF1 (HGNC:20220): (FCF1 rRNA-processing protein) Enables RNA binding activity. Predicted to be involved in rRNA processing. Predicted to act upstream of or within endonucleolytic cleavage in 5'-ETS of tricistronic rRNA transcript (SSU-rRNA, 5.8S rRNA, LSU-rRNA) and endonucleolytic cleavage in ITS1 to separate SSU-rRNA from 5.8S rRNA and LSU-rRNA from tricistronic rRNA transcript (SSU-rRNA, 5.8S rRNA, LSU-rRNA). Predicted to be located in nucleoplasm. Predicted to be part of small-subunit processome. Predicted to be active in nucleolus. [provided by Alliance of Genome Resources, Apr 2022]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 3 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.769
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FCF1 | NM_015962.5 | c.284A>G | p.Tyr95Cys | missense_variant | 4/8 | ENST00000341162.8 | |
FCF1 | NM_001318508.2 | c.248A>G | p.Tyr83Cys | missense_variant | 4/8 | ||
FCF1 | XM_011536815.4 | c.212A>G | p.Tyr71Cys | missense_variant | 3/7 | ||
FCF1 | XM_011536816.4 | c.176A>G | p.Tyr59Cys | missense_variant | 3/7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FCF1 | ENST00000341162.8 | c.284A>G | p.Tyr95Cys | missense_variant | 4/8 | 1 | NM_015962.5 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
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32
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251190Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135760
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GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461474Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2AN XY: 727064
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GnomAD4 genome Cov.: 32
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32
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 09, 2023 | The c.284A>G (p.Y95C) alteration is located in exon 4 (coding exon 4) of the FCF1 gene. This alteration results from a A to G substitution at nucleotide position 284, causing the tyrosine (Y) at amino acid position 95 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D;D;D
M_CAP
Benign
D
MetaRNN
Pathogenic
D;D;D;D
MetaSVM
Uncertain
D
MutationTaster
Benign
D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D;D;D;D
REVEL
Pathogenic
Sift
Benign
T;D;D;D
Sift4G
Uncertain
D;T;T;T
Polyphen
0.99, 0.14
.;D;.;B
Vest4
0.89, 0.89, 0.87
MutPred
0.48
.;Gain of ubiquitination at K97 (P = 0.0716);.;.;
MVP
MPC
0.30
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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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