chr10-70404496-A-T

Variant names:

• chr10-70404496-A-T
• rs1844947142
• NM_004096.5:c.95A>T

Variant summary

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

The NM_004096.5(EIF4EBP2):​c.95A>T​(p.His32Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000138 in 1,447,060 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H32P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: EIF4EBP2 NM_004096.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.90
• Publications: 0 publications found

Genes affected

EIF4EBP2 (HGNC:3289): (eukaryotic translation initiation factor 4E binding protein 2) This gene encodes a member of the eukaryotic translation initiation factor 4E binding protein family. The gene products of this family bind eIF4E and inhibit translation initiation. However, insulin and other growth factors can release this inhibition via a phosphorylation-dependent disruption of their binding to eIF4E. Regulation of protein production through these gene products have been implicated in cell proliferation, cell differentiation and viral infection. [provided by RefSeq, Oct 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EIF4EBP2	NM_004096.5	c.95A>T	p.His32Leu	missense_variant	Exon 1 of 3	ENST00000373218.5	NP_004087.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EIF4EBP2	ENST00000373218.5	c.95A>T	p.His32Leu	missense_variant	Exon 1 of 3	1	NM_004096.5	ENSP00000362314.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1447060 Hom.: 0 Cov.: 32 AF XY: 0.00000139 AC XY: 1 AN XY: 719976

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 31066

American (AMR) AF: 0.00 AC: 0 AN: 44080

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25664

East Asian (EAS) AF: 0.00 AC: 0 AN: 38054

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85136

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51890

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4386

European-Non Finnish (NFE) AF: 9.03e-7 AC: 1 AN: 1107098

Other (OTH) AF: 0.00 AC: 0 AN: 59686

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	0.0087	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	22
DANN	Benign	0.95
DEOGEN2	Uncertain	0.55	D
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.11
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.76	T
M_CAP	Pathogenic	0.47	D
MetaRNN	Uncertain	0.46	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		3.9
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-3.2	D
REVEL	Benign	0.16
Sift	Benign	0.22	T
Sift4G	Benign	0.41	T
Polyphen		0.049	B
Vest4		0.52
MutPred		0.40		Loss of disorder (P = 0.1124);
MVP		0.50
MPC		0.60
ClinPred		0.93	D
GERP RS		2.6
PromoterAI		-0.19	Neutral
Varity_R		0.28
gMVP		0.60
Mutation Taster		=58/42	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

dbSNP: rs1844947142; hg19: chr10-72164252;