NM_020365.5:c.80T>A

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5

The NM_020365.5(EIF2B3):c.80T>A(p.Leu27Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,874 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. L27L) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

EIF2B3
NM_020365.5 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 8.86

Publications

5 publications found

Variant links:

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

EIF2B3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.971

PP5

Variant 1-44981089-A-T is Pathogenic according to our data. Variant chr1-44981089-A-T is described in CliVar as Pathogenic. Clinvar id is 40179.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-44981089-A-T is described in CliVar as Pathogenic. Clinvar id is 40179.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-44981089-A-T is described in CliVar as Pathogenic. Clinvar id is 40179.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-44981089-A-T is described in CliVar as Pathogenic. Clinvar id is 40179.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-44981089-A-T is described in CliVar as Pathogenic. Clinvar id is 40179.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-44981089-A-T is described in CliVar as Pathogenic. Clinvar id is 40179.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-44981089-A-T is described in CliVar as Pathogenic. Clinvar id is 40179.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-44981089-A-T is described in CliVar as Pathogenic. Clinvar id is 40179.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-44981089-A-T is described in CliVar as Pathogenic. Clinvar id is 40179.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-44981089-A-T is described in CliVar as Pathogenic. Clinvar id is 40179.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-44981089-A-T is described in CliVar as Pathogenic. Clinvar id is 40179.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-44981089-A-T is described in CliVar as Pathogenic. Clinvar id is 40179.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-44981089-A-T is described in CliVar as Pathogenic. Clinvar id is 40179.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-44981089-A-T is described in CliVar as Pathogenic. Clinvar id is 40179.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-44981089-A-T is described in CliVar as Pathogenic. Clinvar id is 40179.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EIF2B3	NM_020365.5 link	c.80T>A	p.Leu27Gln	missense_variant	Exon 2 of 12	ENST00000360403.7	NP_065098.1	Q9NR50-1Q9HA31

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EIF2B3	ENST00000360403.7 link	c.80T>A	p.Leu27Gln	missense_variant	Exon 2 of 12	1	NM_020365.5	ENSP00000353575.2		Q9NR50-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461874

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727236

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39694

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1112006

Other (OTH)

AF:

0.00

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Leukoencephalopathy with vanishing white matter 3

Pathogenic:1

Aug 01, 2011

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.43

BayesDel_addAF

Pathogenic

0.56

BayesDel_noAF

Pathogenic

0.57

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.89

.;D;.

Eigen

Pathogenic

0.91

Eigen_PC

Pathogenic

0.82

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.90

D;D;D

M_CAP

Pathogenic

0.58

MetaRNN

Pathogenic

0.97

D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.8

H;H;H

PhyloP100

8.9

PrimateAI

Uncertain

0.50

PROVEAN

Pathogenic

-5.3

.;D;D

REVEL

Pathogenic

0.94

Sift

Uncertain

0.0010

.;D;D

Sift4G

Pathogenic

0.0010

D;D;D

Polyphen

1.0

D;D;D

Vest4

0.87

MutPred

0.83

Gain of disorder (P = 0.0144);Gain of disorder (P = 0.0144);Gain of disorder (P = 0.0144);

MVP

0.99

MPC

0.92

ClinPred

1.0

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.96

gMVP

0.81

Mutation Taster

=2/98

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over