12-123621401-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001414.4(EIF2B1):c.*355G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.235 in 349,914 control chromosomes in the GnomAD database, including 10,484 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.22 (4029 hom., cov: 32)
  • Exomes 𝑓: 0.25 (6455 hom.)
• Consequence: EIF2B1 NM_001414.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0280

Genes affected

EIF2B1 (HGNC:3257): (eukaryotic translation initiation factor 2B subunit alpha) 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, Oct 2009]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 12-123621401-C-T is Benign according to our data. Variant chr12-123621401-C-T is described in ClinVar as [Benign]. Clinvar id is 307524.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.263 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EIF2B1	NM_001414.4	c.*355G>A		3_prime_UTR_variant	9/9	ENST00000424014.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EIF2B1	ENST00000424014.7	c.*355G>A		3_prime_UTR_variant	9/9	1	NM_001414.4	P1

Frequencies

GnomAD3 genomes AF: 0.221 AC: 33556 AN: 151978 Hom.: 4030 Cov.: 32

Gnomad AFR AF: 0.170

Gnomad AMI AF: 0.388

Gnomad AMR AF: 0.221

Gnomad ASJ AF: 0.241

Gnomad EAS AF: 0.0166

Gnomad SAS AF: 0.250

Gnomad FIN AF: 0.187

Gnomad MID AF: 0.299

Gnomad NFE AF: 0.266

Gnomad OTH AF: 0.234

GnomAD4 exome AF: 0.246 AC: 48613 AN: 197818 Hom.: 6455 Cov.: 0 AF XY: 0.250 AC XY: 26872 AN XY: 107644

Gnomad4 AFR exome AF: 0.169

Gnomad4 AMR exome AF: 0.194

Gnomad4 ASJ exome AF: 0.231

Gnomad4 EAS exome AF: 0.0141

Gnomad4 SAS exome AF: 0.269

Gnomad4 FIN exome AF: 0.185

Gnomad4 NFE exome AF: 0.268

Gnomad4 OTH exome AF: 0.242

GnomAD4 genome AF: 0.221 AC: 33555 AN: 152096 Hom.: 4029 Cov.: 32 AF XY: 0.220 AC XY: 16328 AN XY: 74376

Gnomad4 AFR AF: 0.170

Gnomad4 AMR AF: 0.221

Gnomad4 ASJ AF: 0.241

Gnomad4 EAS AF: 0.0168

Gnomad4 SAS AF: 0.250

Gnomad4 FIN AF: 0.187

Gnomad4 NFE AF: 0.266

Gnomad4 OTH AF: 0.231

Alfa AF: 0.241 Hom.: 1039

Bravo AF: 0.217

Asia WGS AF: 0.122 AC: 429 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Vanishing white matter disease Benign:1

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	-0.80
Cadd	Benign	2.6
Dann	Benign	0.60
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs1050443; hg19: chr12-124105948;