rs113994024

chr1-44881722-C-Gchr1-44881722-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Moderate

The NM_020365.5(EIF2B3):c.674G>C(p.Arg225Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R225Q) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: EIF2B3 NM_020365.5 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.67

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]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM1: In a turn (size 3) in uniprot entity EI2BG_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_020365.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-44881722-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 4437.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.846
• PP5: Variant 1-44881722-C-G is Pathogenic according to our data. Variant chr1-44881722-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 1285271.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EIF2B3	NM_020365.5	c.674G>C	p.Arg225Pro	missense_variant	7/12	ENST00000360403.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EIF2B3	ENST00000360403.7	c.674G>C	p.Arg225Pro	missense_variant	7/12	1	NM_020365.5	P1
EIF2B3	ENST00000372183.7	c.674G>C	p.Arg225Pro	missense_variant	7/10	1
EIF2B3	ENST00000620860.4	c.674G>C	p.Arg225Pro	missense_variant	7/11	1
EIF2B3	ENST00000439363.5	c.137G>C	p.Arg46Pro	missense_variant	3/7	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Vanishing white matter disease Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
Cadd	Pathogenic	31
Dann	Uncertain	1.0
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D;D
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.85	D;D;D
MetaSVM	Uncertain	0.56	D
MutationAssessor	Uncertain	2.5	M;M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.70	T
Sift4G	Uncertain	0.0040	D;D;D
Polyphen		1.0	D;P;D
Vest4		0.94
MutPred		0.54		Gain of helix (P = 0.0143);Gain of helix (P = 0.0143);Gain of helix (P = 0.0143);
MVP		0.99
MPC		1.0
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.89
gMVP		0.89

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-45347394;