5-176645970-T-C

Position:

• chr5-176645970-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001099408.2(EIF4E1B):​c.719T>C​(p.Phe240Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: EIF4E1B NM_001099408.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.67

Genes affected

EIF4E1B (HGNC:33179): (eukaryotic translation initiation factor 4E family member 1B) Predicted to enable RNA 7-methylguanosine cap binding activity and translation initiation factor activity. Predicted to be involved in regulation of translation and translational initiation. Predicted to be located in cytoplasm. Predicted to be part of eukaryotic translation initiation factor 4F complex and mRNA cap binding activity complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.839

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EIF4E1B	NM_001099408.2	c.719T>C	p.Phe240Ser	missense_variant	9/9	ENST00000318682.11	NP_001092878.1
EIF4E1B	NM_001375362.1	c.719T>C	p.Phe240Ser	missense_variant	9/9		NP_001362291.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EIF4E1B	ENST00000318682.11	c.719T>C	p.Phe240Ser	missense_variant	9/9	5	NM_001099408.2	ENSP00000323714	P1

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 15, 2023

The c.719T>C (p.F240S) alteration is located in exon 9 (coding exon 7) of the EIF4E1B gene. This alteration results from a T to C substitution at nucleotide position 719, causing the phenylalanine (F) at amino acid position 240 to be replaced by a serine (S). 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	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Uncertain	0.0
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	T;T;T
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.68	.;T;.
M_CAP	Uncertain	0.097	D
MetaRNN	Pathogenic	0.84	D;D;D
MetaSVM	Uncertain	-0.043	T
MutationAssessor	Uncertain	2.8	M;M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-6.1	.;D;D
REVEL	Uncertain	0.49
Sift	Uncertain	0.0010	.;D;D
Sift4G	Uncertain	0.0020	.;D;D
Polyphen		1.0	D;D;D
Vest4		0.86, 0.86
MutPred		0.70		Loss of stability (P = 0.0152);Loss of stability (P = 0.0152);Loss of stability (P = 0.0152);
MVP		0.84
MPC		1.2
ClinPred		0.99	D
GERP RS		5.2
Varity_R		0.84
gMVP		0.43

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-176072971;