18-48619734-C-T

Variant summary

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

The NM_014772.3(CTIF):c.169C>T(p.His57Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00000138 in 1,444,412 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CTIF NM_014772.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.89

Genes affected

CTIF (HGNC:23925): (cap binding complex dependent translation initiation factor) CTIF is a component of the CBP80 (NCBP1; MIM 600469)/CBP20 (NCBP2; MIM 605133) translation initiation complex that binds cotranscriptionally to the cap end of nascent mRNA. The CBP80/CBP20 complex is involved in a simultaneous editing and translation step that recognizes premature termination codons (PTCs) in mRNAs and directs PTC-containing mRNAs toward nonsense-mediated decay (NMD). On mRNAs without PTCs, the CBP80/CBP20 complex is replaced with cytoplasmic mRNA cap-binding proteins, including EIF4G (MIM 600495), and steady-state translation of the mRNAs resumes in the cytoplasm (Kim et al., 2009 [PubMed 19648179]).[supplied by OMIM, Dec 2009]

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=0.13480687).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CTIF	NM_014772.3	c.169C>T	p.His57Tyr	missense_variant	2/12	ENST00000256413.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CTIF	ENST00000256413.8	c.169C>T	p.His57Tyr	missense_variant	2/12	1	NM_014772.3	A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1444412 Hom.: 0 Cov.: 30 AF XY: 0.00000139 AC XY: 1 AN XY: 716880

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000237

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000257

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 20, 2023

The c.169C>T (p.H57Y) alteration is located in exon 3 (coding exon 1) of the CTIF gene. This alteration results from a C to T substitution at nucleotide position 169, causing the histidine (H) at amino acid position 57 to be replaced by a tyrosine (Y). 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	0.089
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
Cadd	Uncertain	23
Dann	Uncertain	0.99
DEOGEN2	Benign	0.026	T;.;.;T;T;.
Eigen	Benign	-0.066
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.97	D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.13	T;T;T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.55	N;N;.;.;.;.
MutationTaster	Benign	0.82	D;D
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.1	N;N;.;.;.;.
REVEL	Benign	0.051
Sift	Uncertain	0.0070	D;D;.;.;.;.
Sift4G	Benign	0.29	T;T;T;T;T;T
Polyphen		0.13	B;B;.;.;.;.
Vest4		0.34
MutPred		0.17		Gain of phosphorylation at H57 (P = 0.0845);Gain of phosphorylation at H57 (P = 0.0845);Gain of phosphorylation at H57 (P = 0.0845);Gain of phosphorylation at H57 (P = 0.0845);Gain of phosphorylation at H57 (P = 0.0845);Gain of phosphorylation at H57 (P = 0.0845);
MVP		0.15
MPC		0.29
ClinPred		0.71	D
GERP RS		4.3
Varity_R		0.21
gMVP		0.12

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

Publications

LitVar

Other links and lift over

dbSNP: rs1307269245; hg19: chr18-46146105; COSMIC: COSV99060941; COSMIC: COSV99060941;