18-48758133-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_014772.3(CTIF):c.799G>A(p.Ala267Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000973 in 1,614,016 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000085 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000099 (0 hom.)
• Consequence: CTIF NM_014772.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.708

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 Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.005952388).
• BP6: Variant 18-48758133-G-A is Benign according to our data. Variant chr18-48758133-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2364805.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CTIF	NM_014772.3	c.799G>A	p.Ala267Thr	missense_variant	8/12	ENST00000256413.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CTIF	ENST00000256413.8	c.799G>A	p.Ala267Thr	missense_variant	8/12	1	NM_014772.3	A1
CTIF	ENST00000382998.8	c.799G>A	p.Ala267Thr	missense_variant	9/13	1		P3
CTIF	ENST00000587769.1	n.451G>A		non_coding_transcript_exon_variant	3/3	4

Frequencies

GnomAD3 genomes AF: 0.0000855 AC: 13 AN: 152072 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000623

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000199 AC: 50 AN: 250934 Hom.: 0 AF XY: 0.000287 AC XY: 39 AN XY: 135690

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00150

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000882

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000985 AC: 144 AN: 1461826 Hom.: 0 Cov.: 32 AF XY: 0.000131 AC XY: 95 AN XY: 727212

Gnomad4 AFR exome AF: 0.000358

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00130

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000108

Gnomad4 OTH exome AF: 0.0000993

GnomAD4 genome AF: 0.0000854 AC: 13 AN: 152190 Hom.: 0 Cov.: 32 AF XY: 0.0000941 AC XY: 7 AN XY: 74404

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.000623

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000564 Hom.: 0

Bravo AF: 0.0000756

ExAC AF: 0.000198 AC: 24

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 08, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.81
Cadd	Benign	1.2
Dann	Benign	0.88
DEOGEN2	Benign	0.010	T;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.016	N
M_CAP	Benign	0.0022	T
MetaRNN	Benign	0.0060	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.14	N;N
REVEL	Benign	0.019
Sift	Benign	0.61	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;B
Vest4		0.048
MVP		0.14
MPC		0.15
ClinPred		0.0055	T
GERP RS		-5.4
Varity_R		0.027
gMVP		0.10

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: rs202032754; hg19: chr18-46284504; COSMIC: COSV56484793; COSMIC: COSV56484793;