12-123621361-A-G

Position:

• chr12-123621361-A-G

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.*395T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.285 in 332,506 control chromosomes in the GnomAD database, including 14,932 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.30 (7704 hom., cov: 32)
  • Exomes 𝑓: 0.27 (7228 hom.)
• Consequence: EIF2B1 NM_001414.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.17

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=-0.88).
• BP6: Variant 12-123621361-A-G is Benign according to our data. Variant chr12-123621361-A-G is described in ClinVar as [Benign]. Clinvar id is 307522.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.413 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EIF2B1	NM_001414.4	c.*395T>C		3_prime_UTR_variant	9/9	ENST00000424014.7	NP_001405.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EIF2B1	ENST00000424014.7	c.*395T>C		3_prime_UTR_variant	9/9	1	NM_001414.4	ENSP00000416250	P1

Frequencies

GnomAD3 genomes AF: 0.303 AC: 46058 AN: 152024 Hom.: 7683 Cov.: 32

Gnomad AFR AF: 0.418

Gnomad AMI AF: 0.389

Gnomad AMR AF: 0.261

Gnomad ASJ AF: 0.261

Gnomad EAS AF: 0.0171

Gnomad SAS AF: 0.281

Gnomad FIN AF: 0.194

Gnomad MID AF: 0.320

Gnomad NFE AF: 0.284

Gnomad OTH AF: 0.289

GnomAD4 exome AF: 0.270 AC: 48648 AN: 180364 Hom.: 7228 Cov.: 0 AF XY: 0.274 AC XY: 26869 AN XY: 98004

Gnomad4 AFR exome AF: 0.426

Gnomad4 AMR exome AF: 0.214

Gnomad4 ASJ exome AF: 0.249

Gnomad4 EAS exome AF: 0.0143

Gnomad4 SAS exome AF: 0.303

Gnomad4 FIN exome AF: 0.190

Gnomad4 NFE exome AF: 0.280

Gnomad4 OTH exome AF: 0.270

GnomAD4 genome AF: 0.303 AC: 46123 AN: 152142 Hom.: 7704 Cov.: 32 AF XY: 0.299 AC XY: 22250 AN XY: 74376

Gnomad4 AFR AF: 0.419

Gnomad4 AMR AF: 0.261

Gnomad4 ASJ AF: 0.261

Gnomad4 EAS AF: 0.0174

Gnomad4 SAS AF: 0.281

Gnomad4 FIN AF: 0.194

Gnomad4 NFE AF: 0.284

Gnomad4 OTH AF: 0.285

Alfa AF: 0.283 Hom.: 2451

Bravo AF: 0.310

Asia WGS AF: 0.156 AC: 546 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

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	-0.88
CADD	Benign	0.069
DANN	Benign	0.55

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: rs1050449; hg19: chr12-124105908;