3-184140584-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 6P and 1B. PM1 PM2 PM5 BP4

The NM_003907.3(EIF2B5):c.1010A>T(p.His337Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,894 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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. H337R) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: EIF2B5 NM_003907.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.89

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a strand (size 2) in uniprot entity EI2BE_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in NM_003907.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-184140584-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 590971.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.32191533).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EIF2B5	NM_003907.3	c.1010A>T	p.His337Leu	missense_variant	7/16	ENST00000648915.2
EIF2B5	XM_047449148.1	c.1010A>T	p.His337Leu	missense_variant	7/11
EIF2B5	XM_011513265.1	c.260A>T	p.His87Leu	missense_variant	3/12
EIF2B5	XM_011513266.4	c.173A>T	p.His58Leu	missense_variant	2/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EIF2B5	ENST00000648915.2	c.1010A>T	p.His337Leu	missense_variant	7/16		NM_003907.3	P2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251454 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135896

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461894 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

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	0.19	D
BayesDel_noAF	Uncertain	0.13
Cadd	Benign	21
Dann	Benign	0.84
DEOGEN2	Benign	0.064	T;.;T
Eigen	Benign	-0.050
Eigen_PC	Benign	0.19
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Benign	0.075	D
MetaRNN	Benign	0.32	T;T;T
MetaSVM	Benign	-0.30	T
MutationAssessor	Benign	0.74	N;.;N
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.92	N;.;.
REVEL	Uncertain	0.39
Sift	Benign	0.96	T;.;.
Sift4G	Benign	0.69	T;.;.
Polyphen		0.013	B;.;B
Vest4		0.75
MutPred		0.41		Loss of disorder (P = 0.0216);.;Loss of disorder (P = 0.0216);
MVP		0.90
MPC		0.35
ClinPred		0.43	T
GERP RS		5.8
Varity_R		0.62
gMVP		0.76

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

LitVar

Other links and lift over

dbSNP: rs907041830; hg19: chr3-183858372;