14-74714904-A-T

Variant names:

• chr14-74714904-A-T
• NM_015962.5:c.104A>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_015962.5(FCF1):​c.104A>T​(p.Lys35Ile) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign 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: 4.09

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17510533).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FCF1	NM_015962.5	c.104A>T	p.Lys35Ile	missense_variant	Exon 3 of 8	ENST00000341162.8	NP_057046.1
FCF1	NM_001318508.2	c.68A>T	p.Lys23Ile	missense_variant	Exon 3 of 8		NP_001305437.1
FCF1	XM_011536815.4	c.72-1047A>T		intron_variant	Intron 2 of 6		XP_011535117.1
FCF1	XM_011536816.4	c.36-1047A>T		intron_variant	Intron 2 of 6		XP_011535118.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FCF1	ENST00000341162.8	c.104A>T	p.Lys35Ile	missense_variant	Exon 3 of 8	1	NM_015962.5	ENSP00000344393.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 10, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.104A>T (p.K35I) alteration is located in exon 3 (coding exon 3) of the FCF1 gene. This alteration results from a A to T substitution at nucleotide position 104, causing the lysine (K) at amino acid position 35 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	0.16
BayesDel_addAF	Uncertain	0.044	T
BayesDel_noAF	Benign	-0.17
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.37	T;T;T
Eigen	Benign	0.029
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.18	T;T;T
MetaSVM	Benign	-0.74	T
MutationAssessor	Pathogenic	3.0	M;.;.
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-3.6	D;D;D
REVEL	Benign	0.28
Sift	Benign	0.057	T;D;D
Sift4G	Uncertain	0.016	D;D;D
Polyphen		0.22	B;.;B
Vest4		0.37
MutPred		0.30		Loss of methylation at K35 (P = 0.0027);.;.;
MVP		0.24
MPC		0.28
ClinPred		0.99	D
GERP RS		3.0
Varity_R		0.35
gMVP		0.47

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: chr14-75181607;