3-184135283-C-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The ENST00000491144.5(EIF2B5):n.246C>G 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 0.0236 in 1,483,838 control chromosomes in the GnomAD database, including 499 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.018 (42 hom., cov: 33)
  • Exomes 𝑓: 0.024 (457 hom.)
• Consequence: EIF2B5 ENST00000491144.5 non_coding_transcript_exon
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.225

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 Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0183 (2781/152364) while in subpopulation NFE AF= 0.0263 (1791/68050). AF 95% confidence interval is 0.0253. There are 42 homozygotes in gnomad4. There are 1283 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
• BS2: High Homozygotes in GnomAd at 42 AR gene

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.246C>G		non_coding_transcript_exon_variant	1/15	2
EIF2B5-DT	ENST00000608135.1			upstream_gene_variant		5

Frequencies

GnomAD3 genomes AF: 0.0183 AC: 2782 AN: 152246 Hom.: 42 Cov.: 33

Gnomad AFR AF: 0.00569

Gnomad AMI AF: 0.0219

Gnomad AMR AF: 0.0198

Gnomad ASJ AF: 0.0599

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0128

Gnomad FIN AF: 0.00791

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.0263

Gnomad OTH AF: 0.0273

GnomAD4 exome AF: 0.0243 AC: 32297 AN: 1331474 Hom.: 457 Cov.: 22 AF XY: 0.0244 AC XY: 16084 AN XY: 659334

Gnomad4 AFR exome AF: 0.00542

Gnomad4 AMR exome AF: 0.0147

Gnomad4 ASJ exome AF: 0.0579

Gnomad4 EAS exome AF: 0.0000282

Gnomad4 SAS exome AF: 0.0141

Gnomad4 FIN exome AF: 0.0117

Gnomad4 NFE exome AF: 0.0263

Gnomad4 OTH exome AF: 0.0258

GnomAD4 genome AF: 0.0183 AC: 2781 AN: 152364 Hom.: 42 Cov.: 33 AF XY: 0.0172 AC XY: 1283 AN XY: 74502

Gnomad4 AFR AF: 0.00565

Gnomad4 AMR AF: 0.0197

Gnomad4 ASJ AF: 0.0599

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0133

Gnomad4 FIN AF: 0.00791

Gnomad4 NFE AF: 0.0263

Gnomad4 OTH AF: 0.0270

Alfa AF: 0.0205 Hom.: 4

Bravo AF: 0.0189

Asia WGS AF: 0.00606 AC: 23 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

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
Cadd	Benign	2.4
Dann	Benign	0.77

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: rs146922950; hg19: chr3-183853071;