chr12-123621292-T-C

Position:

• chr12-123621292-T-C

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.*464A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.363 in 255,610 control chromosomes in the GnomAD database, including 19,757 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.40 (13808 hom., cov: 30)
  • Exomes 𝑓: 0.31 (5949 hom.)
• Consequence: EIF2B1 NM_001414.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.60

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=-0.86).
• BP6: Variant 12-123621292-T-C is Benign according to our data. Variant chr12-123621292-T-C is described in ClinVar as [Benign]. Clinvar id is 307518.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.617 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EIF2B1	NM_001414.4	c.*464A>G		3_prime_UTR_variant	9/9	ENST00000424014.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EIF2B1	ENST00000424014.7	c.*464A>G		3_prime_UTR_variant	9/9	1	NM_001414.4	P1

Frequencies

GnomAD3 genomes AF: 0.397 AC: 60373 AN: 152090 Hom.: 13775 Cov.: 30

Gnomad AFR AF: 0.623

Gnomad AMI AF: 0.431

Gnomad AMR AF: 0.302

Gnomad ASJ AF: 0.331

Gnomad EAS AF: 0.106

Gnomad SAS AF: 0.402

Gnomad FIN AF: 0.239

Gnomad MID AF: 0.377

Gnomad NFE AF: 0.331

Gnomad OTH AF: 0.375

GnomAD4 exome AF: 0.313 AC: 32390 AN: 103402 Hom.: 5949 Cov.: 0 AF XY: 0.320 AC XY: 17537 AN XY: 54722

Gnomad4 AFR exome AF: 0.618

Gnomad4 AMR exome AF: 0.227

Gnomad4 ASJ exome AF: 0.283

Gnomad4 EAS exome AF: 0.0944

Gnomad4 SAS exome AF: 0.398

Gnomad4 FIN exome AF: 0.214

Gnomad4 NFE exome AF: 0.309

Gnomad4 OTH exome AF: 0.310

GnomAD4 genome AF: 0.397 AC: 60460 AN: 152208 Hom.: 13808 Cov.: 30 AF XY: 0.393 AC XY: 29236 AN XY: 74410

Gnomad4 AFR AF: 0.623

Gnomad4 AMR AF: 0.302

Gnomad4 ASJ AF: 0.331

Gnomad4 EAS AF: 0.106

Gnomad4 SAS AF: 0.402

Gnomad4 FIN AF: 0.239

Gnomad4 NFE AF: 0.331

Gnomad4 OTH AF: 0.378

Alfa AF: 0.341 Hom.: 3367

Bravo AF: 0.406

Asia WGS AF: 0.286 AC: 995 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	-0.86
CADD	Benign	0.047
DANN	Benign	0.43

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: rs9919; hg19: chr12-124105839;