14-74734127-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_015962.5(FCF1):​c.505C>T​(p.Arg169Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000229 in 1,613,488 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 (★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

FCF1
NM_015962.5 missense

Scores

7
10
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.99
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 Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.973

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
FCF1NM_015962.5 linkc.505C>T p.Arg169Cys missense_variant Exon 7 of 8 ENST00000341162.8 NP_057046.1 Q9Y324Q4FZ45
FCF1NM_001318508.2 linkc.469C>T p.Arg157Cys missense_variant Exon 7 of 8 NP_001305437.1 G3V1S4
FCF1XM_011536815.4 linkc.433C>T p.Arg145Cys missense_variant Exon 6 of 7 XP_011535117.1
FCF1XM_011536816.4 linkc.397C>T p.Arg133Cys 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.505C>T p.Arg169Cys missense_variant Exon 7 of 8 1 NM_015962.5 ENSP00000344393.4 Q9Y324

Frequencies

GnomAD3 genomes
AF:
0.0000395
AC:
6
AN:
152052
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000262
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000192
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000279
AC:
7
AN:
251278
Hom.:
0
AF XY:
0.0000295
AC XY:
4
AN XY:
135806
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000109
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.0000462
Gnomad NFE exome
AF:
0.0000352
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000212
AC:
31
AN:
1461436
Hom.:
0
Cov.:
29
AF XY:
0.0000206
AC XY:
15
AN XY:
727066
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000504
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.0000187
Gnomad4 NFE exome
AF:
0.0000243
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000395
AC:
6
AN:
152052
Hom.:
0
Cov.:
32
AF XY:
0.0000539
AC XY:
4
AN XY:
74276
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.000262
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000192
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000453
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.00
AC:
0
ExAC
AF:
0.0000247
AC:
3

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Aug 26, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.505C>T (p.R169C) alteration is located in exon 7 (coding exon 7) of the FCF1 gene. This alteration results from a C to T substitution at nucleotide position 505, causing the arginine (R) at amino acid position 169 to be replaced by a cysteine (C). 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
1.0
BayesDel_addAF
Uncertain
0.060
T
BayesDel_noAF
Uncertain
0.070
CADD
Uncertain
24
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.62
D;T;T
Eigen
Uncertain
0.51
Eigen_PC
Uncertain
0.42
FATHMM_MKL
Uncertain
0.88
D
LIST_S2
Uncertain
0.93
D;D;D
M_CAP
Benign
0.040
D
MetaRNN
Pathogenic
0.97
D;D;D
MetaSVM
Uncertain
0.65
D
MutationAssessor
Pathogenic
4.8
H;.;.
PrimateAI
Pathogenic
0.90
D
PROVEAN
Pathogenic
-7.4
D;D;D
REVEL
Pathogenic
0.77
Sift
Uncertain
0.0080
D;D;D
Sift4G
Pathogenic
0.0
D;D;D
Polyphen
0.46
P;.;D
Vest4
0.83
MutPred
0.93
Loss of MoRF binding (P = 0.0041);.;.;
MVP
0.40
MPC
0.26
ClinPred
0.99
D
GERP RS
3.4
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.61
gMVP
0.76

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.21
Details are displayed if max score is > 0.2
DS_DL_spliceai
0.21
Position offset: 43

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: rs769520160; hg19: chr14-75200830; COSMIC: COSV62044211; COSMIC: COSV62044211; API