5-176645868-G-T

Variant names:

• chr5-176645868-G-T
• rs369631741
• NM_001099408.2:c.617G>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001099408.2(EIF4E1B):​c.617G>T​(p.Arg206Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000157 in 1,587,544 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/23 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R206G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000085 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000084 (0 hom.)
• Consequence: EIF4E1B NM_001099408.2 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.851

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

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.06825122).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EIF4E1B	NM_001099408.2	c.617G>T	p.Arg206Leu	missense_variant, splice_region_variant	Exon 9 of 9	ENST00000318682.11	NP_001092878.1
EIF4E1B	NM_001375362.1	c.617G>T	p.Arg206Leu	missense_variant, splice_region_variant	Exon 9 of 9		NP_001362291.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EIF4E1B	ENST00000318682.11	c.617G>T	p.Arg206Leu	missense_variant, splice_region_variant	Exon 9 of 9	5	NM_001099408.2	ENSP00000323714.6
EIF4E1B	ENST00000504597.5	c.617G>T	p.Arg206Leu	missense_variant, splice_region_variant	Exon 9 of 9	5		ENSP00000427633.1

Frequencies

GnomAD3 genomes AF: 0.0000789 AC: 12 AN: 152068 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000290

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000337 AC: 7 AN: 207682 AF XY: 0.0000178

Gnomad AFR exome AF: 0.000499

Gnomad AMR exome AF: 0.0000337

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000836 AC: 12 AN: 1435358 Hom.: 0 Cov.: 31 AF XY: 0.00000702 AC XY: 5 AN XY: 711878

Gnomad4 AFR exome AF: 0.000337 AC: 11 AN: 32644

Gnomad4 AMR exome AF: 0.0000248 AC: 1 AN: 40266

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 25574

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 38124

Gnomad4 SAS exome AF: 0.00 AC: 0 AN: 82586

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 51816

Gnomad4 NFE exome AF: 0.00 AC: 0 AN: 1099202

Gnomad4 Remaining exome AF: 0.00 AC: 0 AN: 59424

GnomAD4 genome AF: 0.0000854 AC: 13 AN: 152186 Hom.: 0 Cov.: 32 AF XY: 0.0000806 AC XY: 6 AN XY: 74402

Gnomad4 AFR AF: 0.000313 AC: 0.000313283 AN: 0.000313283

Gnomad4 AMR AF: 0.00 AC: 0 AN: 0

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.00 AC: 0 AN: 0

Gnomad4 OTH AF: 0.00 AC: 0 AN: 0

Alfa AF: 0.0000254 Hom.: 0

Bravo AF: 0.0000756

ESP6500AA AF: 0.000262 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000249 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 07, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.617G>T (p.R206L) alteration is located in exon 9 (coding exon 7) of the EIF4E1B gene. This alteration results from a G to T substitution at nucleotide position 617, causing the arginine (R) at amino acid position 206 to be replaced by a leucine (L). 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	0.17
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	T;T;T
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.48	N
LIST_S2	Uncertain	0.90	.;D;.
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.068	T;T;T
MetaSVM	Benign	-0.86	T
MutationAssessor	Uncertain	2.2	M;M;M
PrimateAI	Benign	0.18	T
PROVEAN	Pathogenic	-5.0	.;D;D
REVEL	Benign	0.13
Sift	Benign	0.10	.;T;T
Sift4G	Benign	0.14	.;T;T
Polyphen		0.21	B;B;B
Vest4		0.48, 0.48
MVP		0.54
MPC		0.55
ClinPred		0.16	T
GERP RS		1.1
Varity_R		0.15
gMVP		0.48
Mutation Taster		=87/13	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

Publications

LitVar

Other links and lift over

dbSNP: rs369631741; hg19: chr5-176072869;