rs1057520047

Positions:

• chr3-184138004-G-A

Variant summary

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

The NM_003907.3(EIF2B5):​c.613G>A​(p.Val205Met) 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. 16/21 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: EIF2B5 NM_003907.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 1.19

Genes affected

EIF2B5 (HGNC:3261): (eukaryotic translation initiation factor 2B subunit epsilon) This gene encodes one of five subunits of eukaryotic translation initiation factor 2B (EIF2B), a GTP exchange factor for eukaryotic initiation factor 2 and an essential regulator for protein synthesis. Mutations in this gene and the genes encoding other EIF2B subunits have been associated with leukoencephalopathy with vanishing white matter. [provided by RefSeq, Nov 2009]

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=0.07635933).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EIF2B5	NM_003907.3	c.613G>A	p.Val205Met	missense_variant	4/16	ENST00000648915.2
EIF2B5	XM_047449148.1	c.613G>A	p.Val205Met	missense_variant	4/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EIF2B5	ENST00000648915.2	c.613G>A	p.Val205Met	missense_variant	4/16		NM_003907.3	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251240 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135814

Gnomad AFR exome AF: 0.0000616

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Nov 18, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 13, 2022	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 205 of the EIF2B5 protein (p.Val205Met). This variant is present in population databases (no rsID available, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with EIF2B5-related conditions. ClinVar contains an entry for this variant (Variation ID: 376766). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt EIF2B5 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Vanishing white matter disease Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Jan 11, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	15
DANN	Benign	0.93
DEOGEN2	Benign	0.089	T;.;T
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.29
FATHMM_MKL	Benign	0.48	N
LIST_S2	Benign	0.86	.;D;D
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.076	T;T;T
MetaSVM	Benign	-0.39	T
MutationAssessor	Benign	-0.40	N;.;N
MutationTaster	Benign	0.95	N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.81	N;.;.
REVEL	Benign	0.19
Sift	Benign	0.36	T;.;.
Sift4G	Benign	0.49	T;.;.
Polyphen		0.031	B;.;B
Vest4		0.16
MutPred		0.20		Loss of glycosylation at S207 (P = 0.067);.;Loss of glycosylation at S207 (P = 0.067);
MVP		0.41
MPC		0.29
ClinPred		0.044	T
GERP RS		2.5
Varity_R		0.086
gMVP		0.24

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs1057520047; hg19: chr3-183855792;