chr12-123621378-G-A

Position:

• chr12-123621378-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001414.4(EIF2B1):​c.*378C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.279 in 341,188 control chromosomes in the GnomAD database, including 14,422 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.29 (6838 hom., cov: 32)
  • Exomes 𝑓: 0.27 (7584 hom.)
• Consequence: EIF2B1 NM_001414.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.351

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 12-123621378-G-A is Benign according to our data. Variant chr12-123621378-G-A is described in ClinVar as [Benign]. Clinvar id is 307523.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.359 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EIF2B1	NM_001414.4	c.*378C>T		3_prime_UTR_variant	9/9	ENST00000424014.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EIF2B1	ENST00000424014.7	c.*378C>T		3_prime_UTR_variant	9/9	1	NM_001414.4	P1

Frequencies

GnomAD3 genomes AF: 0.288 AC: 43785 AN: 151968 Hom.: 6831 Cov.: 32

Gnomad AFR AF: 0.364

Gnomad AMI AF: 0.394

Gnomad AMR AF: 0.255

Gnomad ASJ AF: 0.257

Gnomad EAS AF: 0.0170

Gnomad SAS AF: 0.279

Gnomad FIN AF: 0.195

Gnomad MID AF: 0.316

Gnomad NFE AF: 0.285

Gnomad OTH AF: 0.280

GnomAD4 exome AF: 0.272 AC: 51475 AN: 189102 Hom.: 7584 Cov.: 0 AF XY: 0.277 AC XY: 28434 AN XY: 102808

Gnomad4 AFR exome AF: 0.371

Gnomad4 AMR exome AF: 0.216

Gnomad4 ASJ exome AF: 0.250

Gnomad4 EAS exome AF: 0.0147

Gnomad4 SAS exome AF: 0.306

Gnomad4 FIN exome AF: 0.195

Gnomad4 NFE exome AF: 0.286

Gnomad4 OTH exome AF: 0.270

GnomAD4 genome AF: 0.288 AC: 43814 AN: 152086 Hom.: 6838 Cov.: 32 AF XY: 0.285 AC XY: 21179 AN XY: 74366

Gnomad4 AFR AF: 0.364

Gnomad4 AMR AF: 0.255

Gnomad4 ASJ AF: 0.257

Gnomad4 EAS AF: 0.0172

Gnomad4 SAS AF: 0.279

Gnomad4 FIN AF: 0.195

Gnomad4 NFE AF: 0.285

Gnomad4 OTH AF: 0.276

Alfa AF: 0.284 Hom.: 5980

Bravo AF: 0.292

Asia WGS AF: 0.148 AC: 518 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 12, 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	-0.72
CADD	Benign	6.2
DANN	Benign	0.91

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: rs1050448; hg19: chr12-124105925;