Genetic Variant EIF2D:p.Leu561Phe (chr1-206593622-G-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_006893.3(EIF2D):c.1681C>T(p.Leu561Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000482 in 1,453,782 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

EIF2D
NM_006893.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.62

Variant links:

Genes affected

EIF2D (HGNC:6583): (eukaryotic translation initiation factor 2D) This gene encodes a translation initiation factor involved in the recruitment and delivery of aminoacyl-tRNAs to the P-site of the eukaryotic ribosome in a GTP-independent manner. This gene was previously referred to as ligatin, but is now known to localize to the cytoplasm and localize and function with translation factors. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2011]

EIF2D links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.39616698).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EIF2D	NM_006893.3 link	c.1681C>T	p.Leu561Phe	missense_variant	Exon 14 of 15	ENST00000271764.7	NP_008824.2	P41214-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
EIF2D	ENST00000271764.7 link	c.1681C>T	p.Leu561Phe	missense_variant	Exon 14 of 15	1	NM_006893.3	ENSP00000271764.2	P41214-1
EIF2D	ENST00000367114.7 link	c.1309C>T	p.Leu437Phe	missense_variant	Exon 12 of 13	1		ENSP00000356081.3	P41214-2
EIF2D	ENST00000472709.6 link	n.138+2096C>T		intron_variant	Intron 2 of 5	5		ENSP00000484299.1	A0A087X1L6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000402

AC:

AN:

248878

Hom.:

AF XY:

0.00

AC XY:

AN XY:

134424

show subpopulations

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000890

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000482

AC:

AN:

1453782

Hom.:

Cov.:

AF XY:

0.00000554

AC XY:

AN XY:

721918

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000633

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 31, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1681C>T (p.L561F) alteration is located in exon 14 (coding exon 14) of the EIF2D gene. This alteration results from a C to T substitution at nucleotide position 1681, causing the leucine (L) at amino acid position 561 to be replaced by a phenylalanine (F). 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

-0.069

BayesDel_noAF

Benign

-0.34

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.083

T;.

Eigen

Uncertain

0.50

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.82

T;T

M_CAP

Benign

0.021

MetaRNN

Benign

0.40

T;T

MetaSVM

Benign

-0.73

MutationAssessor

Uncertain

2.6

M;.

PrimateAI

Benign

0.42

PROVEAN

Benign

-2.1

N;N

REVEL

Benign

0.20

Sift

Uncertain

0.019

D;D

Sift4G

Uncertain

0.017

D;D

Polyphen

0.99

D;P

Vest4

0.32

MutPred

0.55

Loss of helix (P = 0.0104);.;

MVP

0.51

MPC

1.0

ClinPred

0.84

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.28

gMVP

0.34

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over