Genetic Variant FCF1:p.Val71Ile (chr14-74716018-G-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_015962.5(FCF1):c.211G>A(p.Val71Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000744 in 1,613,530 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000099 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000072 ( 0 hom. )

Consequence

FCF1
NM_015962.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.57

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 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.13558969).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FCF1	NM_015962.5 link	c.211G>A	p.Val71Ile	missense_variant	Exon 4 of 8	ENST00000341162.8	NP_057046.1	Q9Y324Q4FZ45
FCF1	NM_001318508.2 link	c.175G>A	p.Val59Ile	missense_variant	Exon 4 of 8		NP_001305437.1	G3V1S4
FCF1	XM_011536815.4 link	c.139G>A	p.Val47Ile	missense_variant	Exon 3 of 7		XP_011535117.1
FCF1	XM_011536816.4 link	c.103G>A	p.Val35Ile	missense_variant	Exon 3 of 7		XP_011535118.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FCF1	ENST00000341162.8 link	c.211G>A	p.Val71Ile	missense_variant	Exon 4 of 8	1	NM_015962.5	ENSP00000344393.4		Q9Y324

Frequencies

GnomAD3 genomes

AF:

0.0000988

AC:

AN:

151852

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000197

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000665

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000147

AC:

AN:

251382

Hom.:

AF XY:

0.0000810

AC XY:

AN XY:

135854

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000781

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000231

Gnomad NFE exome

AF:

0.0000440

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000718

AC:

105

AN:

1461678

Hom.:

Cov.:

AF XY:

0.0000674

AC XY:

AN XY:

727146

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000581

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000356

Gnomad4 NFE exome

AF:

0.0000522

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000988

AC:

AN:

151852

Hom.:

Cov.:

AF XY:

0.000135

AC XY:

AN XY:

74116

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.000197

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000665

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000860

Hom.:

Bravo

AF:

0.0000680

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 05, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.211G>A (p.V71I) alteration is located in exon 4 (coding exon 4) of the FCF1 gene. This alteration results from a G to A substitution at nucleotide position 211, causing the valine (V) at amino acid position 71 to be replaced by an isoleucine (I). 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

Benign

0.15

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.34

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.078

T;T;T

Eigen

Benign

0.018

Eigen_PC

Uncertain

0.24

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.88

D;D;D

M_CAP

Benign

0.012

MetaRNN

Benign

0.14

T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

0.59

N;.;.

PrimateAI

Uncertain

0.70

PROVEAN

Benign

-0.24

N;N;N

REVEL

Benign

0.096

Sift

Benign

0.30

T;T;T

Sift4G

Benign

0.36

T;T;T

Polyphen

0.016

B;.;B

Vest4

0.26

MVP

0.17

MPC

0.13

ClinPred

0.078

GERP RS

5.4

Varity_R

0.079

gMVP

0.44

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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