12-123621404-G-C

Variant names:

• chr12-123621404-G-C
• rs150711091
• NM_001414.4:c.*352C>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001414.4(EIF2B1):​c.*352C>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 0.000793 in 349,308 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00069 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00087 (4 hom.)
• Consequence: EIF2B1 NM_001414.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.368
• Publications: 0 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 12-123621404-G-C is Benign according to our data. Variant chr12-123621404-G-C is described in ClinVar as Benign. ClinVar VariationId is 307525.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000689 (105/152332) while in subpopulation EAS AF = 0.0187 (97/5186). AF 95% confidence interval is 0.0157. There are 1 homozygotes in GnomAd4. There are 59 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

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.*352C>G		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.*352C>G		3_prime_UTR	Exon 9 of 9	ENSP00000416250.2	Q14232-1
	EIF2B1	ENST00000929734.1		c.*352C>G		3_prime_UTR	Exon 10 of 10	ENSP00000599793.1
	EIF2B1	ENST00000857210.1		c.*352C>G		3_prime_UTR	Exon 10 of 10	ENSP00000527269.1

Frequencies

GnomAD3 genomes AF: 0.000696 AC: 106 AN: 152214 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0189

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD4 exome AF: 0.000873 AC: 172 AN: 196976 Hom.: 4 Cov.: 0 AF XY: 0.00101 AC XY: 108 AN XY: 107120

African (AFR) AF: 0.00 AC: 0 AN: 5426

American (AMR) AF: 0.00 AC: 0 AN: 9816

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 4754

East Asian (EAS) AF: 0.0177 AC: 146 AN: 8236

South Asian (SAS) AF: 0.000419 AC: 16 AN: 38182

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8824

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 698

European-Non Finnish (NFE) AF: 0.0000180 AC: 2 AN: 111326

Other (OTH) AF: 0.000824 AC: 8 AN: 9714

GnomAD4 genome AF: 0.000689 AC: 105 AN: 152332 Hom.: 1 Cov.: 32 AF XY: 0.000792 AC XY: 59 AN XY: 74492

African (AFR) AF: 0.00 AC: 0 AN: 41580

American (AMR) AF: 0.000131 AC: 2 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.0187 AC: 97 AN: 5186

South Asian (SAS) AF: 0.000829 AC: 4 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68034

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.000347 Hom.: 0

Bravo AF: 0.000767

Asia WGS AF: 0.00346 AC: 12 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Vanishing white matter disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.77
DANN	Benign	0.48
PhyloP100		-0.37
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs150711091; hg19: chr12-124105951;