Genetic Variant FCF1:p.Ile110Thr (chr14-74723308-T-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_015962.5(FCF1):c.329T>C(p.Ile110Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000089 in 1,461,432 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000089 ( 0 hom. )

Consequence

FCF1
NM_015962.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.86

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]

FCF1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FCF1	NM_015962.5 link	c.329T>C	p.Ile110Thr	missense_variant	Exon 5 of 8	ENST00000341162.8	NP_057046.1	Q9Y324Q4FZ45
FCF1	NM_001318508.2 link	c.293T>C	p.Ile98Thr	missense_variant	Exon 5 of 8		NP_001305437.1	G3V1S4
FCF1	XM_011536815.4 link	c.257T>C	p.Ile86Thr	missense_variant	Exon 4 of 7		XP_011535117.1
FCF1	XM_011536816.4 link	c.221T>C	p.Ile74Thr	missense_variant	Exon 4 of 7		XP_011535118.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FCF1	ENST00000341162.8 link	c.329T>C	p.Ile110Thr	missense_variant	Exon 5 of 8	1	NM_015962.5	ENSP00000344393.4		Q9Y324

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000796

AC:

AN:

251412

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135878

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000890

AC:

AN:

1461432

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

727026

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

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:

0.0000108

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000282

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 08, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.329T>C (p.I110T) alteration is located in exon 5 (coding exon 5) of the FCF1 gene. This alteration results from a T to C substitution at nucleotide position 329, causing the isoleucine (I) at amino acid position 110 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

0.79

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Uncertain

0.050

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.40

.;T;T;T

Eigen

Benign

0.037

Eigen_PC

Uncertain

0.28

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.86

D;D;D;D

M_CAP

Benign

0.0035

MetaRNN

Uncertain

0.73

D;D;D;D

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.81

.;L;.;.

PrimateAI

Pathogenic

0.89

PROVEAN

Uncertain

-3.1

D;D;D;D

REVEL

Uncertain

0.34

Sift

Benign

0.045

D;D;D;D

Sift4G

Uncertain

0.020

D;T;T;T

Polyphen

0.0, 0.0010

.;B;.;B

Vest4

0.81, 0.81, 0.79

MutPred

0.81

.;Loss of stability (P = 0.0709);.;.;

MVP

0.43

MPC

0.20

ClinPred

0.72

GERP RS

6.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.16

gMVP

0.81

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over