12-123626387-G-T

Variant names:

• chr12-123626387-G-T
• rs3704
• NM_001414.4:c.551+38C>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.551+38C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0535 in 1,612,310 control chromosomes in the GnomAD database, including 3,089 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.073 (574 hom., cov: 32)
  • Exomes 𝑓: 0.051 (2515 hom.)
• Consequence: EIF2B1 NM_001414.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0980
• Publications: 12 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

  Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp
• leukoencephalopathy with vanishing white matter 1

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• 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=-0.85).
• BP6: Variant 12-123626387-G-T is Benign according to our data. Variant chr12-123626387-G-T is described in ClinVar as Benign. ClinVar VariationId is 258092.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.132 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EIF2B1	NM_001414.4	c.551+38C>A		intron_variant	Intron 6 of 8	ENST00000424014.7	NP_001405.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EIF2B1	ENST00000424014.7	c.551+38C>A		intron_variant	Intron 6 of 8	1	NM_001414.4	ENSP00000416250.2
EIF2B1	ENST00000537073.1	c.*470C>A		3_prime_UTR_variant	Exon 5 of 5	2		ENSP00000444183.1
EIF2B1	ENST00000539951.5	c.512+38C>A		intron_variant	Intron 5 of 6	5		ENSP00000438060.1
EIF2B1	ENST00000534960.5	c.415-1525C>A		intron_variant	Intron 4 of 5	5		ENSP00000443172.1

Frequencies

GnomAD3 genomes AF: 0.0728 AC: 11073 AN: 152132 Hom.: 565 Cov.: 32

Gnomad AFR AF: 0.135

Gnomad AMI AF: 0.0384

Gnomad AMR AF: 0.0325

Gnomad ASJ AF: 0.0461

Gnomad EAS AF: 0.0877

Gnomad SAS AF: 0.118

Gnomad FIN AF: 0.0449

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.0462

Gnomad OTH AF: 0.0655

GnomAD2 exomes AF: 0.0618 AC: 15515 AN: 251116 AF XY: 0.0628

Gnomad AFR exome AF: 0.137

Gnomad AMR exome AF: 0.0197

Gnomad ASJ exome AF: 0.0475

Gnomad EAS exome AF: 0.0918

Gnomad FIN exome AF: 0.0466

Gnomad NFE exome AF: 0.0486

Gnomad OTH exome AF: 0.0495

GnomAD4 exome AF: 0.0514 AC: 75089 AN: 1460060 Hom.: 2515 Cov.: 30 AF XY: 0.0533 AC XY: 38731 AN XY: 726454

African (AFR) AF: 0.136 AC: 4555 AN: 33434

American (AMR) AF: 0.0215 AC: 960 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.0452 AC: 1180 AN: 26120

East Asian (EAS) AF: 0.0713 AC: 2829 AN: 39684

South Asian (SAS) AF: 0.116 AC: 10006 AN: 86214

European-Finnish (FIN) AF: 0.0444 AC: 2370 AN: 53368

Middle Eastern (MID) AF: 0.0402 AC: 232 AN: 5764

European-Non Finnish (NFE) AF: 0.0446 AC: 49537 AN: 1110464

Other (OTH) AF: 0.0567 AC: 3420 AN: 60308

GnomAD4 genome AF: 0.0730 AC: 11107 AN: 152250 Hom.: 574 Cov.: 32 AF XY: 0.0724 AC XY: 5390 AN XY: 74440

African (AFR) AF: 0.135 AC: 5609 AN: 41528

American (AMR) AF: 0.0324 AC: 496 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0461 AC: 160 AN: 3470

East Asian (EAS) AF: 0.0869 AC: 450 AN: 5178

South Asian (SAS) AF: 0.118 AC: 568 AN: 4820

European-Finnish (FIN) AF: 0.0449 AC: 476 AN: 10608

Middle Eastern (MID) AF: 0.0578 AC: 17 AN: 294

European-Non Finnish (NFE) AF: 0.0462 AC: 3140 AN: 68032

Other (OTH) AF: 0.0738 AC: 156 AN: 2114

Alfa AF: 0.0641 Hom.: 80

Bravo AF: 0.0725

Asia WGS AF: 0.128 AC: 443 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	1.7
DANN	Benign	0.60
PhyloP100		-0.098
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: rs3704; hg19: chr12-124110934;