rs7602534

Positions:

chr2-27369556-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBA1

The NM_001034116.2(EIF2B4):c.76-7G>A variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.388 in 1,613,406 control chromosomes in the GnomAD database, including 125,028 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.41 ( 13164 hom., cov: 32)

Exomes 𝑓: 0.39 ( 111864 hom. )

Consequence

EIF2B4
NM_001034116.2 splice_region, splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.0003890

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 1.28

Variant links:

Genes affected

EIF2B4 (HGNC:3260): (eukaryotic translation initiation factor 2B subunit delta) Eukaryotic initiation factor 2B (EIF2B), which is necessary for protein synthesis, is a GTP exchange factor composed of five different subunits. The protein encoded by this gene is the fourth, or delta, subunit. Defects in this gene are a cause of leukoencephalopathy with vanishing white matter (VWM) and ovarioleukodystrophy. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

EIF2B4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.37).

BP6

Variant 2-27369556-C-T is Benign according to our data. Variant chr2-27369556-C-T is described in ClinVar as [Benign]. Clinvar id is 95738.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-27369556-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.477 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EIF2B4	NM_001034116.2 linkuse as main transcript	c.76-7G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000347454.9	NP_001029288.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EIF2B4	ENST00000347454.9 linkuse as main transcript	c.76-7G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_001034116.2	ENSP00000233552	P4	Q9UI10-1

Frequencies

GnomAD3 genomes

AF:

0.408

AC:

61985

AN:

151866

Hom.:

13131

Cov.:

show subpopulations

Gnomad AFR

AF:

0.483

Gnomad AMI

AF:

0.220

Gnomad AMR

AF:

0.449

Gnomad ASJ

AF:

0.329

Gnomad EAS

AF:

0.149

Gnomad SAS

AF:

0.402

Gnomad FIN

AF:

0.429

Gnomad MID

AF:

0.363

Gnomad NFE

AF:

0.379

Gnomad OTH

AF:

0.371

GnomAD3 exomes

AF:

0.398

AC:

100015

AN:

251384

Hom.:

21279

AF XY:

0.391

AC XY:

53104

AN XY:

135870

show subpopulations

Gnomad AFR exome

AF:

0.483

Gnomad AMR exome

AF:

0.553

Gnomad ASJ exome

AF:

0.333

Gnomad EAS exome

AF:

0.147

Gnomad SAS exome

AF:

0.400

Gnomad FIN exome

AF:

0.428

Gnomad NFE exome

AF:

0.379

Gnomad OTH exome

AF:

0.387

GnomAD4 exome

AF:

0.386

AC:

564162

AN:

1461422

Hom.:

111864

Cov.:

AF XY:

0.385

AC XY:

279597

AN XY:

727030

show subpopulations

Gnomad4 AFR exome

AF:

0.485

Gnomad4 AMR exome

AF:

0.543

Gnomad4 ASJ exome

AF:

0.333

Gnomad4 EAS exome

AF:

0.131

Gnomad4 SAS exome

AF:

0.397

Gnomad4 FIN exome

AF:

0.432

Gnomad4 NFE exome

AF:

0.385

Gnomad4 OTH exome

AF:

0.374

GnomAD4 genome

AF:

0.408

AC:

62074

AN:

151984

Hom.:

13164

Cov.:

AF XY:

0.408

AC XY:

30333

AN XY:

74304

show subpopulations

Gnomad4 AFR

AF:

0.483

Gnomad4 AMR

AF:

0.450

Gnomad4 ASJ

AF:

0.329

Gnomad4 EAS

AF:

0.150

Gnomad4 SAS

AF:

0.403

Gnomad4 FIN

AF:

0.429

Gnomad4 NFE

AF:

0.379

Gnomad4 OTH

AF:

0.375

Alfa

AF:

0.378

Hom.:

26064

Bravo

AF:

0.414

Asia WGS

AF:

0.339

AC:

1179

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 13, 2017	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 26, 2019	This variant is associated with the following publications: (PMID: 28008009) -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 19, 2014	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Vanishing white matter disease

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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_noAF

Benign

-0.37

CADD

Benign

DANN

Benign

0.87

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00039

dbscSNV1_RF

Benign

0.042

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

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