rs113994063

Variant names:

• chr3-184140517-C-G
• rs113994063
• NM_003907.3:c.943C>G

Your query was ambiguous. Multiple possible variants found:

• chr3-184140517-C-G
• chr3-184140517-C-T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PM5 PP3_Moderate

The NM_003907.3(EIF2B5):​c.943C>G​(p.Arg315Gly) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R315C) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: EIF2B5 NM_003907.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.97
• Publications: 11 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-184140517-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 598970.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.906

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EIF2B5	NM_003907.3	c.943C>G	p.Arg315Gly	missense_variant	Exon 7 of 16	ENST00000648915.2	NP_003898.2
EIF2B5	XM_047449148.1	c.943C>G	p.Arg315Gly	missense_variant	Exon 7 of 11		XP_047305104.1
EIF2B5	XM_011513265.1	c.193C>G	p.Arg65Gly	missense_variant	Exon 3 of 12		XP_011511567.1
EIF2B5	XM_011513266.4	c.106C>G	p.Arg36Gly	missense_variant	Exon 2 of 11		XP_011511568.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EIF2B5	ENST00000648915.2	c.943C>G	p.Arg315Gly	missense_variant	Exon 7 of 16		NM_003907.3	ENSP00000497160.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.43
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	T;.;T
Eigen	Benign	0.15
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.86	.;D;D
M_CAP	Uncertain	0.097	D
MetaRNN	Pathogenic	0.91	D;D;D
MetaSVM	Uncertain	0.47	D
MutationAssessor	Benign	1.2	L;.;L
PhyloP100		5.0
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-2.9	D;.;.
REVEL	Pathogenic	0.72
Sift	Benign	0.033	D;.;.
Sift4G	Benign	0.076	T;.;.
Polyphen		0.68	P;.;P
Vest4		0.96
MutPred		0.82		Loss of MoRF binding (P = 0.061);.;Loss of MoRF binding (P = 0.061);
MVP		0.99
MPC		0.37
ClinPred		0.90	D
GERP RS		5.8
Varity_R		0.89
gMVP		0.75
Mutation Taster		=5/95	disease causing

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: rs113994063; hg19: chr3-183858305;