5-176645384-G-A

Variant names:

• chr5-176645384-G-A
• rs199835250
• NM_001099408.2:c.482G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_001099408.2(EIF4E1B):​c.482G>A​(p.Cys161Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000453 in 1,531,854 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00028 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00047 (1 hom.)
• Consequence: EIF4E1B NM_001099408.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.07

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: Uncertain_significance. The variant received 2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.93

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EIF4E1B	NM_001099408.2	c.482G>A	p.Cys161Tyr	missense_variant	Exon 8 of 9	ENST00000318682.11	NP_001092878.1
EIF4E1B	NM_001375362.1	c.482G>A	p.Cys161Tyr	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.482G>A	p.Cys161Tyr	missense_variant	Exon 8 of 9	5	NM_001099408.2	ENSP00000323714.6
EIF4E1B	ENST00000504597.5	c.482G>A	p.Cys161Tyr	missense_variant	Exon 8 of 9	5		ENSP00000427633.1

Frequencies

GnomAD3 genomes AF: 0.000283 AC: 43 AN: 152194 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000544

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000202 AC: 38 AN: 188408 AF XY: 0.000190

Gnomad AFR exome AF: 0.000203

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000559

Gnomad NFE exome AF: 0.000381

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000472 AC: 651 AN: 1379660 Hom.: 1 Cov.: 32 AF XY: 0.000426 AC XY: 288 AN XY: 676410

Gnomad4 AFR exome AF: 0.0000644 AC: 2 AN: 31036

Gnomad4 AMR exome AF: 0.00 AC: 0 AN: 33704

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 20886

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 38720

Gnomad4 SAS exome AF: 0.00 AC: 0 AN: 73320

Gnomad4 FIN exome AF: 0.0000197 AC: 1 AN: 50696

Gnomad4 NFE exome AF: 0.000589 AC: 630 AN: 1069098

Gnomad4 Remaining exome AF: 0.000317 AC: 18 AN: 56808

GnomAD4 genome AF: 0.000283 AC: 43 AN: 152194 Hom.: 0 Cov.: 32 AF XY: 0.000215 AC XY: 16 AN XY: 74344

Gnomad4 AFR AF: 0.0000965 AC: 0.0000965204 AN: 0.0000965204

Gnomad4 AMR AF: 0.0000654 AC: 0.0000654279 AN: 0.0000654279

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: 0.0000942 AC: 0.000094162 AN: 0.000094162

Gnomad4 NFE AF: 0.000544 AC: 0.00054383 AN: 0.00054383

Gnomad4 OTH AF: 0.00 AC: 0 AN: 0

Alfa AF: 0.000328 Hom.: 0

Bravo AF: 0.000264

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000479 AC: 2

ESP6500EA AF: 0.000475 AC: 4

ExAC AF: 0.000208 AC: 25

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 28, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.482G>A (p.C161Y) alteration is located in exon 8 (coding exon 6) of the EIF4E1B gene. This alteration results from a G to A substitution at nucleotide position 482, causing the cysteine (C) at amino acid position 161 to be replaced by a tyrosine (Y). 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	0.66
BayesDel_addAF	Uncertain	0.080	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.21	T;T;T
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.98	.;D;.
M_CAP	Benign	0.054	D
MetaRNN	Pathogenic	0.93	D;D;D
MetaSVM	Uncertain	-0.19	T
MutationAssessor	Pathogenic	3.1	M;M;M
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-10	.;D;D
REVEL	Pathogenic	0.74
Sift	Uncertain	0.0010	.;D;D
Sift4G	Uncertain	0.013	.;D;D
Polyphen		1.0	D;D;D
Vest4		0.90
MVP		0.83
MPC		1.2
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.96
gMVP		0.76
Mutation Taster		=38/62	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs199835250; hg19: chr5-176072385;