rs141872864

Variant names:

• chr2-27369052-T-C
• rs141872864
• NM_001034116.2:c.372A>G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_001034116.2(EIF2B4):​c.372A>G​(p.Gly124Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000329 in 1,614,018 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00034 (4 hom.)
• Consequence: EIF2B4 NM_001034116.2 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 0.0490
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• leukoencephalopathy with vanishing white matter 4

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• leukoencephalopathy with vanishing white matter

  Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp
• leukoencephalopathy with vanishing white matter 1

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• ovarioleukodystrophy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP6: Variant 2-27369052-T-C is Benign according to our data. Variant chr2-27369052-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 585845.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.000343 (501/1461894) while in subpopulation MID AF = 0.00399 (23/5768). AF 95% confidence interval is 0.00272. There are 4 homozygotes in GnomAdExome4. There are 256 alleles in the male GnomAdExome4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001034116.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EIF2B4	NM_001034116.2	MANE Select	c.372A>G	p.Gly124Gly	synonymous	Exon 4 of 13	NP_001029288.1
	EIF2B4	NM_001318965.2		c.435A>G	p.Gly145Gly	synonymous	Exon 3 of 12	NP_001305894.1
	EIF2B4	NM_172195.4		c.432A>G	p.Gly144Gly	synonymous	Exon 3 of 12	NP_751945.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EIF2B4	ENST00000347454.9	TSL:1 MANE Select	c.372A>G	p.Gly124Gly	synonymous	Exon 4 of 13	ENSP00000233552.6
	EIF2B4	ENST00000451130.6	TSL:1	c.432A>G	p.Gly144Gly	synonymous	Exon 3 of 12	ENSP00000394869.2
	EIF2B4	ENST00000445933.6	TSL:1	c.369A>G	p.Gly123Gly	synonymous	Exon 4 of 13	ENSP00000394397.2

Frequencies

GnomAD3 genomes AF: 0.000197 AC: 30 AN: 152006 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000177

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000612 AC: 154 AN: 251494 AF XY: 0.000500

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000809

Gnomad ASJ exome AF: 0.00248

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000439

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.000343 AC: 501 AN: 1461894 Hom.: 4 Cov.: 33 AF XY: 0.000352 AC XY: 256 AN XY: 727248

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.000872 AC: 39 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00249 AC: 65 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000962 AC: 83 AN: 86258

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53420

Middle Eastern (MID) AF: 0.00399 AC: 23 AN: 5768

European-Non Finnish (NFE) AF: 0.000214 AC: 238 AN: 1112012

Other (OTH) AF: 0.000861 AC: 52 AN: 60396

GnomAD4 genome AF: 0.000197 AC: 30 AN: 152124 Hom.: 0 Cov.: 32 AF XY: 0.000242 AC XY: 18 AN XY: 74374

African (AFR) AF: 0.0000482 AC: 2 AN: 41508

American (AMR) AF: 0.000393 AC: 6 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10590

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000177 AC: 12 AN: 67972

Other (OTH) AF: 0.00 AC: 0 AN: 2108

Alfa AF: 0.000457 Hom.: 0

Bravo AF: 0.000253

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000709

EpiControl AF: 0.000296

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	1	-	Vanishing white matter disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	15
DANN	Benign	0.58
PhyloP100		0.049
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.33		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.33		Position offset: 24

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs141872864; hg19: chr2-27591919;