14-74734911-A-T

Variant names:

• chr14-74734911-A-T
• rs369988210
• NM_015962.5:c.578A>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.578A>T​(p.Tyr193Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000342 in 1,461,650 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: FCF1 NM_015962.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.49

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=0.15756044).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FCF1	NM_015962.5	c.578A>T	p.Tyr193Phe	missense_variant	Exon 8 of 8	ENST00000341162.8	NP_057046.1
FCF1	NM_001318508.2	c.542A>T	p.Tyr181Phe	missense_variant	Exon 8 of 8		NP_001305437.1
FCF1	XM_011536815.4	c.506A>T	p.Tyr169Phe	missense_variant	Exon 7 of 7		XP_011535117.1
FCF1	XM_011536816.4	c.470A>T	p.Tyr157Phe	missense_variant	Exon 7 of 7		XP_011535118.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FCF1	ENST00000341162.8	c.578A>T	p.Tyr193Phe	missense_variant	Exon 8 of 8	1	NM_015962.5	ENSP00000344393.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461650 Hom.: 0 Cov.: 29 AF XY: 0.00000550 AC XY: 4 AN XY: 727140

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.00

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: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 16, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.578A>T (p.Y193F) alteration is located in exon 8 (coding exon 8) of the FCF1 gene. This alteration results from a A to T substitution at nucleotide position 578, causing the tyrosine (Y) at amino acid position 193 to be replaced by a phenylalanine (F). 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	0.12
BayesDel_addAF	Uncertain	0.027	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	19
DANN	Benign	0.96
DEOGEN2	Benign	0.039	T;T;T
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.076
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D;D;D
M_CAP	Benign	0.0030	T
MetaRNN	Benign	0.16	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.76	N;.;.
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-0.95	N;N;N
REVEL	Benign	0.15
Sift	Benign	0.63	T;T;T
Sift4G	Benign	0.64	T;T;T
Polyphen		0.0020	B;.;B
Vest4		0.42
MutPred		0.28		Loss of phosphorylation at Y193 (P = 0.0178);.;.;
MVP		0.44
MPC		0.14
ClinPred		0.80	D
GERP RS		4.8
Varity_R		0.12
gMVP		0.43

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

Other links and lift over

dbSNP: rs369988210; hg19: chr14-75201614;