chr11-10801770-A-T

Variant names:

• chr11-10801770-A-T
• NM_001418.4:c.1304T>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001418.4(EIF4G2):​c.1304T>A​(p.Leu435Gln) 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. 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: 33)
• Consequence: EIF4G2 NM_001418.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.99
• Publications: 0 publications found

Genes affected

EIF4G2 (HGNC:3297): (eukaryotic translation initiation factor 4 gamma 2) Translation initiation is mediated by specific recognition of the cap structure by eukaryotic translation initiation factor 4F (eIF4F), which is a cap binding protein complex that consists of three subunits: eIF4A, eIF4E and eIF4G. The protein encoded by this gene shares similarity with the C-terminal region of eIF4G that contains the binding sites for eIF4A and eIF3; eIF4G, in addition, contains a binding site for eIF4E at the N-terminus. Unlike eIF4G, which supports cap-dependent and independent translation, this gene product functions as a general repressor of translation by forming translationally inactive complexes. In vitro and in vivo studies indicate that translation of this mRNA initiates exclusively at a non-AUG (GUG) codon. Alternatively spliced transcript variants encoding different isoforms of this gene have been described. [provided by RefSeq, Jul 2008]

SNORD97 (HGNC:32760): (small nucleolar RNA, C/D box 97)

CTR9 (HGNC:16850): (CTR9 homolog, Paf1/RNA polymerase II complex component) The protein encoded by this gene is a component of the PAF1 complex, which associates with RNA polymerase II and functions in transcriptional regulation and elongation. This complex also plays a role in the modification of histones. [provided by RefSeq, Oct 2016]

CTR9 Gene-Disease associations (from GenCC):

• childhood kidney Wilms tumor

  Inheritance: AD Classification: MODERATE Submitted by: G2P
• CTR9-related neurodevelopmental disorder

  Inheritance: AD Classification: MODERATE Submitted by: G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07249904).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EIF4G2	NM_001418.4	c.1304T>A	p.Leu435Gln	missense_variant	Exon 14 of 22	ENST00000339995.11	NP_001409.3
EIF4G2	NM_001172705.1	c.1304T>A	p.Leu435Gln	missense_variant	Exon 14 of 22		NP_001166176.1
EIF4G2	NM_001042559.3	c.1299+279T>A		intron_variant	Intron 13 of 20		NP_001036024.3
SNORD97	NR_004403.1	n.-162T>A		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EIF4G2	ENST00000339995.11	c.1304T>A	p.Leu435Gln	missense_variant	Exon 14 of 22	1	NM_001418.4	ENSP00000340281.6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 30, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1304T>A (p.L435Q) alteration is located in exon 14 (coding exon 13) of the EIF4G2 gene. This alteration results from a T to A substitution at nucleotide position 1304, causing the leucine (L) at amino acid position 435 to be replaced by a glutamine (Q). 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	0.081
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	20
DANN	Benign	0.91
DEOGEN2	Benign	0.091	.;.;.;T
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.027
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.84	.;.;T;T
MetaRNN	Benign	0.072	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.8	.;.;.;N
PhyloP100		5.0
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	1.2	N;N;N;.
REVEL	Benign	0.069
Sift	Benign	0.48	T;T;T;.
Sift4G	Benign	0.32	T;T;T;.
MutPred		0.24		Gain of loop (P = 0.0079);Gain of loop (P = 0.0079);Gain of loop (P = 0.0079);Gain of loop (P = 0.0079);
MVP		0.15
ClinPred		0.55	D
GERP RS		6.0
Varity_R		0.38
gMVP		0.19
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

hg19: chr11-10823317;