14-74734136-C-A

Variant names:

• chr14-74734136-C-A
• NM_015962.5:c.514C>A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.91

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

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
FCF1	NM_015962.5	c.514C>A	p.Pro172Thr	missense_variant	Exon 7 of 8	ENST00000341162.8	NP_057046.1
FCF1	NM_001318508.2	c.478C>A	p.Pro160Thr	missense_variant	Exon 7 of 8		NP_001305437.1
FCF1	XM_011536815.4	c.442C>A	p.Pro148Thr	missense_variant	Exon 6 of 7		XP_011535117.1
FCF1	XM_011536816.4	c.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
FCF1	ENST00000341162.8	c.514C>A	p.Pro172Thr	missense_variant	Exon 7 of 8	1	NM_015962.5	ENSP00000344393.4

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

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;