14-74734136-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_015962.5(FCF1):​c.514C>A​(p.Pro172Thr) variant causes a missense 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 Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

FCF1
NM_015962.5 missense

Scores

12
4
3

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.91
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.861

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
FCF1NM_015962.5 linkc.514C>A p.Pro172Thr missense_variant Exon 7 of 8 ENST00000341162.8 NP_057046.1 Q9Y324Q4FZ45
FCF1NM_001318508.2 linkc.478C>A p.Pro160Thr missense_variant Exon 7 of 8 NP_001305437.1 G3V1S4
FCF1XM_011536815.4 linkc.442C>A p.Pro148Thr missense_variant Exon 6 of 7 XP_011535117.1
FCF1XM_011536816.4 linkc.406C>A p.Pro136Thr missense_variant Exon 6 of 7 XP_011535118.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
FCF1ENST00000341162.8 linkc.514C>A p.Pro172Thr missense_variant Exon 7 of 8 1 NM_015962.5 ENSP00000344393.4 Q9Y324

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
29
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Jun 11, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.514C>A (p.P172T) alteration is located in exon 7 (coding exon 7) of the FCF1 gene. This alteration results from a C to A substitution at nucleotide position 514, causing the proline (P) at amino acid position 172 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.98
BayesDel_addAF
Pathogenic
0.44
D
BayesDel_noAF
Pathogenic
0.40
CADD
Pathogenic
28
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.53
D;T;T
Eigen
Pathogenic
0.90
Eigen_PC
Pathogenic
0.84
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.97
D;D;D
M_CAP
Benign
0.039
D
MetaRNN
Pathogenic
0.86
D;D;D
MetaSVM
Uncertain
0.46
D
MutationAssessor
Pathogenic
4.0
H;.;.
PrimateAI
Pathogenic
0.87
D
PROVEAN
Pathogenic
-7.7
D;D;D
REVEL
Pathogenic
0.83
Sift
Benign
0.031
D;D;D
Sift4G
Uncertain
0.023
D;D;D
Polyphen
0.96
D;.;P
Vest4
0.84
MutPred
0.77
Gain of phosphorylation at P172 (P = 0.0519);.;.;
MVP
0.46
MPC
0.66
ClinPred
1.0
D
GERP RS
5.3
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.60
gMVP
0.67

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.090
Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-75200839; API