5-176645392-G-C

Variant names:

• chr5-176645392-G-C
• rs773730956
• NM_001099408.2:c.490G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001099408.2(EIF4E1B):​c.490G>C​(p.Gly164Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000163 in 1,529,622 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: EIF4E1B NM_001099408.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.94

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_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.99

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EIF4E1B	NM_001099408.2	c.490G>C	p.Gly164Arg	missense_variant	Exon 8 of 9	ENST00000318682.11	NP_001092878.1
EIF4E1B	NM_001375362.1	c.490G>C	p.Gly164Arg	missense_variant	Exon 8 of 9		NP_001362291.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EIF4E1B	ENST00000318682.11	c.490G>C	p.Gly164Arg	missense_variant	Exon 8 of 9	5	NM_001099408.2	ENSP00000323714.6
EIF4E1B	ENST00000504597.5	c.490G>C	p.Gly164Arg	missense_variant	Exon 8 of 9	5		ENSP00000427633.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152192 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000321 AC: 6 AN: 186676 AF XY: 0.0000303

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000564

Gnomad OTH exome AF: 0.000233

GnomAD4 exome AF: 0.0000174 AC: 24 AN: 1377430 Hom.: 0 Cov.: 31 AF XY: 0.0000222 AC XY: 15 AN XY: 675192

Gnomad4 AFR exome AF: 0.00 AC: 0 AN: 30896

Gnomad4 AMR exome AF: 0.00 AC: 0 AN: 33074

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 20778

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 38708

Gnomad4 SAS exome AF: 0.00 AC: 0 AN: 72992

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 50614

Gnomad4 NFE exome AF: 0.0000215 AC: 23 AN: 1068268

Gnomad4 Remaining exome AF: 0.0000176 AC: 1 AN: 56718

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152192 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74352

Gnomad4 AFR AF: 0.00 AC: 0 AN: 0

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: 0.0000147 AC: 0.0000146998 AN: 0.0000146998

Gnomad4 OTH AF: 0.00 AC: 0 AN: 0

Alfa AF: 0.0000436 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.0000250 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 10, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.490G>C (p.G164R) alteration is located in exon 8 (coding exon 6) of the EIF4E1B gene. This alteration results from a G to C substitution at nucleotide position 490, causing the glycine (G) at amino acid position 164 to be replaced by an arginine (R). 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	0.84
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.50	T;T;T
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.92	.;D;.
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Uncertain	0.59	D
MutationAssessor	Pathogenic	3.8	H;H;H
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-7.4	.;D;D
REVEL	Pathogenic	0.72
Sift	Pathogenic	0.0	.;D;D
Sift4G	Pathogenic	0.0010	.;D;D
Polyphen		1.0	D;D;D
Vest4		0.99
MutPred		0.97		Gain of phosphorylation at S166 (P = 0.0801);Gain of phosphorylation at S166 (P = 0.0801);Gain of phosphorylation at S166 (P = 0.0801);
MVP		0.92
MPC		0.98
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.92
gMVP		0.89
Mutation Taster		=12/88	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs773730956; hg19: chr5-176072393;