chr12-123621401-C-T

Variant names:

• chr12-123621401-C-T
• rs1050443
• NM_001414.4:c.*355G>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.*355G>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 0.235 in 349,914 control chromosomes in the GnomAD database, including 10,484 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (4029 hom., cov: 32)
  • Exomes 𝑓: 0.25 (6455 hom.)
• Consequence: EIF2B1 NM_001414.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0280
• Publications: 8 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: Labcorp Genetics (formerly Invitae), ClinGen
• 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 12-123621401-C-T is Benign according to our data. Variant chr12-123621401-C-T is described in ClinVar as Benign. ClinVar VariationId is 307524.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.263 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.*355G>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.*355G>A		3_prime_UTR	Exon 9 of 9	ENSP00000416250.2	Q14232-1
	EIF2B1	ENST00000929734.1		c.*355G>A		3_prime_UTR	Exon 10 of 10	ENSP00000599793.1
	EIF2B1	ENST00000857210.1		c.*355G>A		3_prime_UTR	Exon 10 of 10	ENSP00000527269.1

Frequencies

GnomAD3 genomes AF: 0.221 AC: 33556 AN: 151978 Hom.: 4030 Cov.: 32

Gnomad AFR AF: 0.170

Gnomad AMI AF: 0.388

Gnomad AMR AF: 0.221

Gnomad ASJ AF: 0.241

Gnomad EAS AF: 0.0166

Gnomad SAS AF: 0.250

Gnomad FIN AF: 0.187

Gnomad MID AF: 0.299

Gnomad NFE AF: 0.266

Gnomad OTH AF: 0.234

GnomAD4 exome AF: 0.246 AC: 48613 AN: 197818 Hom.: 6455 Cov.: 0 AF XY: 0.250 AC XY: 26872 AN XY: 107644

African (AFR) AF: 0.169 AC: 915 AN: 5416

American (AMR) AF: 0.194 AC: 1910 AN: 9858

Ashkenazi Jewish (ASJ) AF: 0.231 AC: 1101 AN: 4776

East Asian (EAS) AF: 0.0141 AC: 116 AN: 8212

South Asian (SAS) AF: 0.269 AC: 10458 AN: 38852

European-Finnish (FIN) AF: 0.185 AC: 1643 AN: 8874

Middle Eastern (MID) AF: 0.291 AC: 202 AN: 694

European-Non Finnish (NFE) AF: 0.268 AC: 29912 AN: 111418

Other (OTH) AF: 0.242 AC: 2356 AN: 9718

GnomAD4 genome AF: 0.221 AC: 33555 AN: 152096 Hom.: 4029 Cov.: 32 AF XY: 0.220 AC XY: 16328 AN XY: 74376

African (AFR) AF: 0.170 AC: 7051 AN: 41476

American (AMR) AF: 0.221 AC: 3380 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.241 AC: 836 AN: 3468

East Asian (EAS) AF: 0.0168 AC: 87 AN: 5180

South Asian (SAS) AF: 0.250 AC: 1205 AN: 4818

European-Finnish (FIN) AF: 0.187 AC: 1981 AN: 10568

Middle Eastern (MID) AF: 0.291 AC: 85 AN: 292

European-Non Finnish (NFE) AF: 0.266 AC: 18090 AN: 67996

Other (OTH) AF: 0.231 AC: 487 AN: 2112

Alfa AF: 0.239 Hom.: 1049

Bravo AF: 0.217

Asia WGS AF: 0.122 AC: 429 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (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	2.6
DANN	Benign	0.60
PhyloP100		0.028
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1050443; hg19: chr12-124105948;