12-123621707-C-T

Variant names:

• chr12-123621707-C-T
• rs61458734
• NM_001414.4:c.*49G>A

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 2 publications found

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]

EIF2B1 Gene-Disease associations (from GenCC):

• leukoencephalopathy with vanishing white matter 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae)
• leukoencephalopathy with vanishing white matter

  Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp
• ovarioleukodystrophy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001414.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EIF2B1	NM_001414.4	MANE Select	c.*49G>A		3_prime_UTR	Exon 9 of 9	NP_001405.1	Q14232-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EIF2B1	ENST00000424014.7	TSL:1 MANE Select	c.*49G>A		3_prime_UTR	Exon 9 of 9	ENSP00000416250.2	Q14232-1
	EIF2B1	ENST00000929734.1		c.*49G>A		3_prime_UTR	Exon 10 of 10	ENSP00000599793.1
	EIF2B1	ENST00000857210.1		c.*49G>A		3_prime_UTR	Exon 10 of 10	ENSP00000527269.1

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

GnomAD2 exomes AF: 0.00629 AC: 1579 AN: 251130 AF XY: 0.00500

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 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

African (AFR) AF: 0.0632 AC: 2111 AN: 33406

American (AMR) AF: 0.00443 AC: 198 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.0314 AC: 820 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000105 AC: 9 AN: 86058

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53330

Middle Eastern (MID) AF: 0.00612 AC: 27 AN: 4412

European-Non Finnish (NFE) AF: 0.000476 AC: 529 AN: 1111660

Other (OTH) AF: 0.00682 AC: 411 AN: 60230

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

African (AFR) AF: 0.0609 AC: 2529 AN: 41522

American (AMR) AF: 0.00739 AC: 113 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0334 AC: 116 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000720 AC: 49 AN: 68036

Other (OTH) AF: 0.0175 AC: 37 AN: 2112

Alfa AF: 0.00716 Hom.: 11

Bravo AF: 0.0214

Asia WGS AF: 0.00491 AC: 17 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)
-	-	1	Vanishing white matter disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.55
DANN	Benign	0.63
PhyloP100		-1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs61458734; hg19: chr12-124106254;