NM_020365.5:c.*401T>C

Variant names:

• chr1-44850550-A-G
• rs116672991
• NM_020365.5:c.*401T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_020365.5(EIF2B3):​c.*401T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00204 in 238,254 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 Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0030 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00031 (0 hom.)
• Consequence: EIF2B3 NM_020365.5 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.533
• Publications: 0 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 3

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 1-44850550-A-G is Benign according to our data. Variant chr1-44850550-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 875157.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00302 (459/152206) while in subpopulation AFR AF = 0.0107 (446/41522). AF 95% confidence interval is 0.00992. There are 2 homozygotes in GnomAd4. There are 237 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020365.5. 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
	EIF2B3	NM_020365.5	MANE Select	c.*401T>C		3_prime_UTR	Exon 12 of 12	NP_065098.1	Q9NR50-1
	EIF2B3	NM_001261418.2		c.*450T>C		3_prime_UTR	Exon 11 of 11	NP_001248347.1	Q9NR50-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EIF2B3	ENST00000360403.7	TSL:1 MANE Select	c.*401T>C		3_prime_UTR	Exon 12 of 12	ENSP00000353575.2	Q9NR50-1
	EIF2B3	ENST00000620860.4	TSL:1	c.*450T>C		3_prime_UTR	Exon 11 of 11	ENSP00000483996.1	Q9NR50-3
	EIF2B3	ENST00000852379.1		c.*401T>C		downstream_gene	N/A	ENSP00000522438.1

Frequencies

GnomAD3 genomes AF: 0.00302 AC: 459 AN: 152088 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.0108

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00239

GnomAD4 exome AF: 0.000314 AC: 27 AN: 86048 Hom.: 0 Cov.: 0 AF XY: 0.000197 AC XY: 9 AN XY: 45712

African (AFR) AF: 0.0105 AC: 25 AN: 2380

American (AMR) AF: 0.000232 AC: 1 AN: 4302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2206

East Asian (EAS) AF: 0.00 AC: 0 AN: 4488

South Asian (SAS) AF: 0.00 AC: 0 AN: 11964

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 3374

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 52494

Other (OTH) AF: 0.000220 AC: 1 AN: 4550

GnomAD4 genome AF: 0.00302 AC: 459 AN: 152206 Hom.: 2 Cov.: 32 AF XY: 0.00319 AC XY: 237 AN XY: 74408

African (AFR) AF: 0.0107 AC: 446 AN: 41522

American (AMR) AF: 0.000458 AC: 7 AN: 15288

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68004

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.00162 Hom.: 0

Bravo AF: 0.00319

ClinVar

ClinVar submissions

Significance: Likely benign

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	-0.82
CADD	Benign	6.0
DANN	Benign	0.79
PhyloP100		0.53

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs116672991; hg19: chr1-45316222;