rs3738248

Variant names:

• chr1-44879774-T-A
• rs3738248
• NM_020365.5:c.975+44A>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_020365.5(EIF2B3):​c.975+44A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.169 in 1,601,584 control chromosomes in the GnomAD database, including 23,102 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (1839 hom., cov: 32)
  • Exomes 𝑓: 0.17 (21263 hom.)
• Consequence: EIF2B3 NM_020365.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.280
• Publications: 4 publications found

Genes affected

EIF2B3 (HGNC:3259): (eukaryotic translation initiation factor 2B subunit gamma) The protein encoded by this gene is one of the subunits of initiation factor eIF2B, which catalyzes the exchange of eukaryotic initiation factor 2-bound GDP for GTP. It has also been found to function as a cofactor of hepatitis C virus internal ribosome entry site-mediated translation. Mutations in this gene have been associated with leukodystrophy with vanishing white matter. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2009]

EIF2B3 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=-0.77).
• BP6: Variant 1-44879774-T-A is Benign according to our data. Variant chr1-44879774-T-A is described in ClinVar as [Benign]. Clinvar id is 261223.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.171 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EIF2B3	NM_020365.5	c.975+44A>T		intron_variant	Intron 8 of 11	ENST00000360403.7	NP_065098.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EIF2B3	ENST00000360403.7	c.975+44A>T		intron_variant	Intron 8 of 11	1	NM_020365.5	ENSP00000353575.2
EIF2B3	ENST00000372183.7	c.975+44A>T		intron_variant	Intron 8 of 9	1		ENSP00000361257.3
EIF2B3	ENST00000620860.4	c.975+44A>T		intron_variant	Intron 8 of 10	1		ENSP00000483996.1
EIF2B3	ENST00000439363.5	c.435+44A>T		intron_variant	Intron 4 of 6	3		ENSP00000396985.1

Frequencies

GnomAD3 genomes AF: 0.150 AC: 22840 AN: 152058 Hom.: 1830 Cov.: 32

Gnomad AFR AF: 0.112

Gnomad AMI AF: 0.180

Gnomad AMR AF: 0.149

Gnomad ASJ AF: 0.165

Gnomad EAS AF: 0.161

Gnomad SAS AF: 0.155

Gnomad FIN AF: 0.143

Gnomad MID AF: 0.0981

Gnomad NFE AF: 0.173

Gnomad OTH AF: 0.140

GnomAD2 exomes AF: 0.162 AC: 40562 AN: 250510 AF XY: 0.162

Gnomad AFR exome AF: 0.114

Gnomad AMR exome AF: 0.155

Gnomad ASJ exome AF: 0.165

Gnomad EAS exome AF: 0.165

Gnomad FIN exome AF: 0.145

Gnomad NFE exome AF: 0.174

Gnomad OTH exome AF: 0.161

GnomAD4 exome AF: 0.170 AC: 247002 AN: 1449406 Hom.: 21263 Cov.: 28 AF XY: 0.170 AC XY: 122581 AN XY: 721714

African (AFR) AF: 0.111 AC: 3685 AN: 33198

American (AMR) AF: 0.152 AC: 6783 AN: 44650

Ashkenazi Jewish (ASJ) AF: 0.167 AC: 4348 AN: 26042

East Asian (EAS) AF: 0.183 AC: 7246 AN: 39660

South Asian (SAS) AF: 0.162 AC: 13935 AN: 85894

European-Finnish (FIN) AF: 0.153 AC: 8163 AN: 53364

Middle Eastern (MID) AF: 0.140 AC: 613 AN: 4370

European-Non Finnish (NFE) AF: 0.175 AC: 192529 AN: 1102366

Other (OTH) AF: 0.162 AC: 9700 AN: 59862

GnomAD4 genome AF: 0.150 AC: 22883 AN: 152178 Hom.: 1839 Cov.: 32 AF XY: 0.149 AC XY: 11104 AN XY: 74412

African (AFR) AF: 0.112 AC: 4668 AN: 41532

American (AMR) AF: 0.149 AC: 2269 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.165 AC: 572 AN: 3468

East Asian (EAS) AF: 0.160 AC: 832 AN: 5186

South Asian (SAS) AF: 0.155 AC: 748 AN: 4814

European-Finnish (FIN) AF: 0.143 AC: 1517 AN: 10598

Middle Eastern (MID) AF: 0.102 AC: 30 AN: 294

European-Non Finnish (NFE) AF: 0.173 AC: 11790 AN: 67984

Other (OTH) AF: 0.138 AC: 293 AN: 2116

Alfa AF: 0.163 Hom.: 361

Bravo AF: 0.151

Asia WGS AF: 0.135 AC: 470 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

May 11, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	7.4
DANN	Benign	0.68
PhyloP100		0.28
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: rs3738248; hg19: chr1-45345446; COSMIC: COSV64517062; COSMIC: COSV64517062;