rs77068026

chr1-44874670-A-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000372183.7(EIF2B3):c.1210T>G(p.Ser404Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.017 in 1,613,938 control chromosomes in the GnomAD database, including 455 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/13 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (68 hom., cov: 32)
  • Exomes 𝑓: 0.017 (387 hom.)
• Consequence: EIF2B3 ENST00000372183.7 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 2.02

Genes affected

EIF2B3 (HGNC:3259): (eukaryotic translation initiation factor 2B subunit gamma) The protein encoded by this gene is one of the subunits of initiation factor eIF2B, which catalyzes the exchange of eukaryotic initiation factor 2-bound GDP for GTP. It has also been found to function as a cofactor of hepatitis C virus internal ribosome entry site-mediated translation. Mutations in this gene have been associated with leukodystrophy with vanishing white matter. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2009]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0020470321).
• BP6: Variant 1-44874670-A-C is Benign according to our data. Variant chr1-44874670-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 95945.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-44874670-A-C is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0527 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EIF2B3	NM_020365.5	c.1202+8T>G		splice_region_variant, intron_variant		ENST00000360403.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EIF2B3	ENST00000360403.7	c.1202+8T>G		splice_region_variant, intron_variant		1	NM_020365.5	P1

Frequencies

GnomAD3 genomes AF: 0.0159 AC: 2420 AN: 152062 Hom.: 68 Cov.: 32

Gnomad AFR AF: 0.00382

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0554

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.000769

Gnomad SAS AF: 0.0100

Gnomad FIN AF: 0.0263

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0153

Gnomad OTH AF: 0.0154

GnomAD3 exomes AF: 0.0218 AC: 5476 AN: 251400 Hom.: 173 AF XY: 0.0190 AC XY: 2582 AN XY: 135872

Gnomad AFR exome AF: 0.00344

Gnomad AMR exome AF: 0.0784

Gnomad ASJ exome AF: 0.00486

Gnomad EAS exome AF: 0.000381

Gnomad SAS exome AF: 0.00918

Gnomad FIN exome AF: 0.0284

Gnomad NFE exome AF: 0.0145

Gnomad OTH exome AF: 0.0188

GnomAD4 exome AF: 0.0171 AC: 25013 AN: 1461758 Hom.: 387 Cov.: 32 AF XY: 0.0166 AC XY: 12037 AN XY: 727174

Gnomad4 AFR exome AF: 0.00293

Gnomad4 AMR exome AF: 0.0781

Gnomad4 ASJ exome AF: 0.00520

Gnomad4 EAS exome AF: 0.000302

Gnomad4 SAS exome AF: 0.00998

Gnomad4 FIN exome AF: 0.0291

Gnomad4 NFE exome AF: 0.0159

Gnomad4 OTH exome AF: 0.0188

GnomAD4 genome AF: 0.0160 AC: 2428 AN: 152180 Hom.: 68 Cov.: 32 AF XY: 0.0164 AC XY: 1222 AN XY: 74410

Gnomad4 AFR AF: 0.00381

Gnomad4 AMR AF: 0.0558

Gnomad4 ASJ AF: 0.00259

Gnomad4 EAS AF: 0.000771

Gnomad4 SAS AF: 0.0102

Gnomad4 FIN AF: 0.0263

Gnomad4 NFE AF: 0.0153

Gnomad4 OTH AF: 0.0152

Alfa AF: 0.0136 Hom.: 9

Bravo AF: 0.0175

TwinsUK AF: 0.0143 AC: 53

ALSPAC AF: 0.0138 AC: 53

ESP6500AA AF: 0.00477 AC: 21

ESP6500EA AF: 0.0149 AC: 128

ExAC AF: 0.0191 AC: 2316

Asia WGS AF: 0.0110 AC: 37 AN: 3478

EpiCase AF: 0.0149

EpiControl AF: 0.0124

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 17, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 14, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Vanishing white matter disease Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.45
Cadd	Benign	11
Dann	Uncertain	0.98
Eigen	Benign	-0.0055
Eigen_PC	Benign	-0.093
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.12	T
MetaRNN	Benign	0.0020	T
MetaSVM	Benign	-0.76	T
MutationTaster	Benign	1.0	N;N
PROVEAN	Benign	0.020	N
REVEL	Benign	0.10
Sift	Benign	0.96	T
Sift4G	Benign	0.86	T
Polyphen		0.0	B
Vest4		0.044
ClinPred		0.0037	T
GERP RS		2.5

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: rs77068026; hg19: chr1-45340342;