12-123621707-C-T

Variant names:

• chr12-123621707-C-T
• rs61458734
• NM_001414.4:c.*49G>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.*49G>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 0.00431 in 1,611,898 control chromosomes in the GnomAD database, including 146 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.019 (73 hom., cov: 32)
  • Exomes 𝑓: 0.0028 (73 hom.)
• Consequence: EIF2B1 NM_001414.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.29

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=-0.8).
• BP6: Variant 12-123621707-C-T is Benign according to our data. Variant chr12-123621707-C-T is described in ClinVar as [Benign]. Clinvar id is 258089.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0589 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EIF2B1	NM_001414.4	c.*49G>A		3_prime_UTR_variant	Exon 9 of 9	ENST00000424014.7	NP_001405.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EIF2B1	ENST00000424014	c.*49G>A		3_prime_UTR_variant	Exon 9 of 9	1	NM_001414.4	ENSP00000416250.2
EIF2B1	ENST00000539951.5	c.*243G>A		downstream_gene_variant		5		ENSP00000438060.1

Frequencies

GnomAD3 genomes AF: 0.0187 AC: 2847 AN: 152142 Hom.: 74 Cov.: 32

Gnomad AFR AF: 0.0611

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00740

Gnomad ASJ AF: 0.0334

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000720

Gnomad OTH AF: 0.0177

GnomAD3 exomes AF: 0.00629 AC: 1579 AN: 251130 Hom.: 38 AF XY: 0.00500 AC XY: 679 AN XY: 135778

Gnomad AFR exome AF: 0.0623

Gnomad AMR exome AF: 0.00451

Gnomad ASJ exome AF: 0.0279

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000924

Gnomad OTH exome AF: 0.00424

GnomAD4 exome AF: 0.00281 AC: 4105 AN: 1459638 Hom.: 73 Cov.: 31 AF XY: 0.00256 AC XY: 1857 AN XY: 726170

Gnomad4 AFR exome AF: 0.0632

Gnomad4 AMR exome AF: 0.00443

Gnomad4 ASJ exome AF: 0.0314

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000105

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000476

Gnomad4 OTH exome AF: 0.00682

GnomAD4 genome AF: 0.0187 AC: 2845 AN: 152260 Hom.: 73 Cov.: 32 AF XY: 0.0189 AC XY: 1406 AN XY: 74456

Gnomad4 AFR AF: 0.0609

Gnomad4 AMR AF: 0.00739

Gnomad4 ASJ AF: 0.0334

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000720

Gnomad4 OTH AF: 0.0175

Alfa AF: 0.00629 Hom.: 6

Bravo AF: 0.0214

Asia WGS AF: 0.00491 AC: 17 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Vanishing white matter disease Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	0.55
DANN	Benign	0.63
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs61458734; hg19: chr12-124106254;