22-31443009-T-A

Position:

• chr22-31443009-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_019843.4(EIF4ENIF1):​c.2159A>T​(p.Lys720Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: EIF4ENIF1 NM_019843.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.77

Genes affected

EIF4ENIF1 (HGNC:16687): (eukaryotic translation initiation factor 4E nuclear import factor 1) The protein encoded by this gene is a nucleocytoplasmic shuttle protein for the translation initiation factor eIF4E. This shuttle protein interacts with the importin alpha-beta complex to mediate nuclear import of eIF4E. It is predominantly cytoplasmic; its own nuclear import is regulated by a nuclear localization signal and nuclear export signals. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2009]

DRG1 (HGNC:3029): (developmentally regulated GTP binding protein 1) Enables several functions, including GTPase activity; identical protein binding activity; and potassium ion binding activity. Involved in positive regulation of microtubule polymerization and regulation of mitotic spindle assembly. Located in cytosol and nuclear body. Part of polysome. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14037472).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EIF4ENIF1	NM_019843.4	c.2159A>T	p.Lys720Ile	missense_variant	16/19	ENST00000330125.10	NP_062817.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EIF4ENIF1	ENST00000330125.10	c.2159A>T	p.Lys720Ile	missense_variant	16/19	1	NM_019843.4	ENSP00000328103	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

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

Apr 10, 2023

The c.2159A>T (p.K720I) alteration is located in exon 16 (coding exon 15) of the EIF4ENIF1 gene. This alteration results from a A to T substitution at nucleotide position 2159, causing the lysine (K) at amino acid position 720 to be replaced by an isoleucine (I). 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	0.23
BayesDel_addAF	Benign	-0.0025	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.24	.;T;T;.
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.10
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.88	D;.;D;D
M_CAP	Benign	0.0085	T
MetaRNN	Benign	0.14	T;T;T;T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	1.6	.;L;L;.
MutationTaster	Benign	0.63	D;D;D;D;D
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.99	N;N;N;N
REVEL	Benign	0.13
Sift	Benign	0.034	D;D;D;D
Sift4G	Uncertain	0.058	T;D;D;D
Polyphen		0.047, 0.24	.;B;B;B
Vest4		0.43
MutPred		0.25		.;Loss of ubiquitination at K720 (P = 0.0118);Loss of ubiquitination at K720 (P = 0.0118);.;
MVP		0.31
MPC		0.32
ClinPred		0.40	T
GERP RS		3.6
Varity_R		0.076
gMVP		0.23

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1004064485; hg19: chr22-31838995;