3-184135269-C-T

Variant names:

• chr3-184135269-C-T
• rs182550783
• ENST00000491144.5:n.232C>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The ENST00000491144.5(EIF2B5):​n.232C>T variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00227 in 1,431,932 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0017 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0023 (2 hom.)
• Consequence: EIF2B5 ENST00000491144.5 non_coding_transcript_exon
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.459
• Publications: 0 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00167 (254/152372) while in subpopulation NFE AF = 0.00306 (208/68038). AF 95% confidence interval is 0.00272. There are 0 homozygotes in GnomAd4. There are 110 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000491144.5. 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.-117C>T		upstream_gene	N/A	NP_003898.2	Q13144
	EIF2B5-DT	NR_183718.1		n.-8G>A		upstream_gene	N/A
	EIF2B5-DT	NR_183719.1		n.-8G>A		upstream_gene	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EIF2B5	ENST00000491144.5	TSL:2	n.232C>T		non_coding_transcript_exon	Exon 1 of 15
	EIF2B5-DT	ENST00000608135.2	TSL:5	n.149G>A		non_coding_transcript_exon	Exon 1 of 3
	EIF2B5-DT	ENST00000608232.6	TSL:5	n.21G>A		non_coding_transcript_exon	Exon 1 of 3

Frequencies

GnomAD3 genomes AF: 0.00167 AC: 254 AN: 152254 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000386

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00113

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00306

Gnomad OTH AF: 0.00143

GnomAD4 exome AF: 0.00234 AC: 2991 AN: 1279560 Hom.: 2 Cov.: 20 AF XY: 0.00234 AC XY: 1490 AN XY: 635736

African (AFR) AF: 0.000240 AC: 7 AN: 29150

American (AMR) AF: 0.000543 AC: 19 AN: 35018

Ashkenazi Jewish (ASJ) AF: 0.000166 AC: 4 AN: 24040

East Asian (EAS) AF: 0.00 AC: 0 AN: 35142

South Asian (SAS) AF: 0.000185 AC: 14 AN: 75660

European-Finnish (FIN) AF: 0.00142 AC: 67 AN: 47342

Middle Eastern (MID) AF: 0.000369 AC: 2 AN: 5426

European-Non Finnish (NFE) AF: 0.00287 AC: 2795 AN: 973776

Other (OTH) AF: 0.00154 AC: 83 AN: 54006

GnomAD4 genome AF: 0.00167 AC: 254 AN: 152372 Hom.: 0 Cov.: 33 AF XY: 0.00148 AC XY: 110 AN XY: 74516

African (AFR) AF: 0.000385 AC: 16 AN: 41590

American (AMR) AF: 0.000915 AC: 14 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.00113 AC: 12 AN: 10624

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

European-Non Finnish (NFE) AF: 0.00306 AC: 208 AN: 68038

Other (OTH) AF: 0.00142 AC: 3 AN: 2116

Alfa AF: 0.00196 Hom.: 0

Bravo AF: 0.00143

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

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	-0.70
CADD	Benign	5.2
DANN	Benign	0.90
PhyloP100		-0.46
PromoterAI		0.036	Neutral
Mutation Taster		=300/0	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: rs182550783; hg19: chr3-183853057;