3-184135269-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The ENST00000491144.5(EIF2B5):n.232C>T variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00227 in 1,431,932 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0017 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0023 (2 hom.)
• Consequence: EIF2B5 ENST00000491144.5 non_coding_transcript_exon
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.459

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]

EIF2B5-DT (HGNC:55202): (EIF2B5 divergent transcript)

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00167 (254/152372) while in subpopulation NFE AF= 0.00306 (208/68038). AF 95% confidence interval is 0.00272. There are 0 homozygotes in gnomad4. There are 110 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EIF2B5-DT	NR_183718.1			upstream_gene_variant
EIF2B5-DT	NR_183719.1			upstream_gene_variant
EIF2B5-DT	NR_183720.1			upstream_gene_variant
EIF2B5-DT	NR_183721.1			upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EIF2B5	ENST00000491144.5	n.232C>T		non_coding_transcript_exon_variant	1/15	2
EIF2B5-DT	ENST00000608135.1			upstream_gene_variant		5

Frequencies

GnomAD3 genomes AF: 0.00167 AC: 254 AN: 152254 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000386

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00113

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00306

Gnomad OTH AF: 0.00143

GnomAD4 exome AF: 0.00234 AC: 2991 AN: 1279560 Hom.: 2 Cov.: 20 AF XY: 0.00234 AC XY: 1490 AN XY: 635736

Gnomad4 AFR exome AF: 0.000240

Gnomad4 AMR exome AF: 0.000543

Gnomad4 ASJ exome AF: 0.000166

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000185

Gnomad4 FIN exome AF: 0.00142

Gnomad4 NFE exome AF: 0.00287

Gnomad4 OTH exome AF: 0.00154

GnomAD4 genome AF: 0.00167 AC: 254 AN: 152372 Hom.: 0 Cov.: 33 AF XY: 0.00148 AC XY: 110 AN XY: 74516

Gnomad4 AFR AF: 0.000385

Gnomad4 AMR AF: 0.000915

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00113

Gnomad4 NFE AF: 0.00306

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00196 Hom.: 0

Bravo AF: 0.00143

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Vanishing white matter disease Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
Cadd	Benign	5.2
Dann	Benign	0.90

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

Other links and lift over

dbSNP: rs182550783; hg19: chr3-183853057;