14-74716025-C-G

Variant names:

• chr14-74716025-C-G
• NM_015962.5:c.218C>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_015962.5(FCF1):​c.218C>G​(p.Thr73Ser) 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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.66
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.788

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015962.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FCF1	NM_015962.5	MANE Select	c.218C>G	p.Thr73Ser	missense	Exon 4 of 8	NP_057046.1	Q9Y324
	FCF1	NM_001318508.2		c.182C>G	p.Thr61Ser	missense	Exon 4 of 8	NP_001305437.1	G3V1S4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FCF1	ENST00000341162.8	TSL:1 MANE Select	c.218C>G	p.Thr73Ser	missense	Exon 4 of 8	ENSP00000344393.4	Q9Y324
	FCF1	ENST00000534938.6	TSL:3	c.182C>G	p.Thr61Ser	missense	Exon 4 of 8	ENSP00000444939.2	G3V1S4
	FCF1	ENST00000553615.5	TSL:3	c.173C>G	p.Thr58Ser	missense	Exon 4 of 8	ENSP00000452497.1	G3V5S9

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.40	T
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.065	D
MetaRNN	Pathogenic	0.79	D
MetaSVM	Uncertain	0.0027	D
MutationAssessor	Pathogenic	3.6	H
PhyloP100		7.7
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-3.8	D
REVEL	Pathogenic	0.74
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.014	D
Polyphen		0.88	P
Vest4		0.90
MutPred		0.65		Gain of relative solvent accessibility (P = 0.09)
MVP		0.55
MPC		0.18
ClinPred		0.99	D
GERP RS		5.4
Varity_R		0.80
gMVP		0.74
Mutation Taster		=28/72	disease causing

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

Other links and lift over

hg19: chr14-75182728;