NM_003907.3:c.1686G>A

Variant names:

• chr3-184143083-G-A
• rs114216498
• NM_003907.3:c.1686G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_003907.3(EIF2B5):​c.1686G>A​(p.Gln562Gln) variant causes a synonymous change. The variant allele was found at a frequency of 0.00309 in 1,613,952 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0022 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0032 (11 hom.)
• Consequence: EIF2B5 NM_003907.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 5.69
• Publications: 5 publications found

Genes affected

EIF2B5 (HGNC:3261): (eukaryotic translation initiation factor 2B subunit epsilon) 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, Nov 2009]

EIF2B5-DT (HGNC:55202): (EIF2B5 divergent transcript)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 3-184143083-G-A is Benign according to our data. Variant chr3-184143083-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 259195.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00217 (330/152346) while in subpopulation AMR AF = 0.00438 (67/15304). AF 95% confidence interval is 0.00354. There are 0 homozygotes in GnomAd4. There are 149 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 11 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003907.3. 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
	EIF2B5	NM_003907.3	MANE Select	c.1686G>A	p.Gln562Gln	synonymous	Exon 12 of 16	NP_003898.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EIF2B5	ENST00000648915.2	MANE Select	c.1686G>A	p.Gln562Gln	synonymous	Exon 12 of 16	ENSP00000497160.1
	EIF2B5	ENST00000481054.5	TSL:1	n.1780G>A		non_coding_transcript_exon	Exon 13 of 15
	EIF2B5	ENST00000647909.1		c.1710G>A	p.Gln570Gln	synonymous	Exon 12 of 16	ENSP00000498164.1

Frequencies

GnomAD3 genomes AF: 0.00217 AC: 330 AN: 152228 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000531

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00438

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00179

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00307

Gnomad OTH AF: 0.00382

GnomAD2 exomes AF: 0.00215 AC: 539 AN: 250890 AF XY: 0.00207

Gnomad AFR exome AF: 0.000499

Gnomad AMR exome AF: 0.00226

Gnomad ASJ exome AF: 0.000498

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00245

Gnomad NFE exome AF: 0.00326

Gnomad OTH exome AF: 0.00245

GnomAD4 exome AF: 0.00319 AC: 4656 AN: 1461606 Hom.: 11 Cov.: 32 AF XY: 0.00304 AC XY: 2210 AN XY: 727084

African (AFR) AF: 0.000598 AC: 20 AN: 33466

American (AMR) AF: 0.00280 AC: 125 AN: 44674

Ashkenazi Jewish (ASJ) AF: 0.000575 AC: 15 AN: 26100

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.000278 AC: 24 AN: 86192

European-Finnish (FIN) AF: 0.00288 AC: 154 AN: 53416

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.00376 AC: 4182 AN: 1111900

Other (OTH) AF: 0.00220 AC: 133 AN: 60390

GnomAD4 genome AF: 0.00217 AC: 330 AN: 152346 Hom.: 0 Cov.: 32 AF XY: 0.00200 AC XY: 149 AN XY: 74500

African (AFR) AF: 0.000529 AC: 22 AN: 41588

American (AMR) AF: 0.00438 AC: 67 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3472

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

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00179 AC: 19 AN: 10622

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

European-Non Finnish (NFE) AF: 0.00307 AC: 209 AN: 68030

Other (OTH) AF: 0.00378 AC: 8 AN: 2114

Alfa AF: 0.00235 Hom.: 0

Bravo AF: 0.00245

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00278

EpiControl AF: 0.00249

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Vanishing white matter disease (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	6.1
DANN	Benign	0.76
PhyloP100		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=92/8	polymorphism

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: rs114216498; hg19: chr3-183860871;