3-184135395-C-T

Variant names:

• chr3-184135395-C-T
• rs767998775
• NM_003907.3:c.10C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_003907.3(EIF2B5):​c.10C>T​(p.Pro4Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000253 in 1,579,066 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. P4P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: EIF2B5 NM_003907.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.65
• Publications: 0 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_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.056138933).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003907.3. 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
	EIF2B5	NM_003907.3	MANE Select	c.10C>T	p.Pro4Ser	missense	Exon 1 of 16	NP_003898.2	Q13144
	EIF2B5-DT	NR_183718.1		n.-134G>A		upstream_gene	N/A
	EIF2B5-DT	NR_183719.1		n.-134G>A		upstream_gene	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EIF2B5	ENST00000648915.2	MANE Select	c.10C>T	p.Pro4Ser	missense	Exon 1 of 16	ENSP00000497160.1	Q13144
	EIF2B5	ENST00000432569.2	TSL:1	c.10C>T	p.Pro4Ser	missense	Exon 1 of 2	ENSP00000414775.1	C9JRD9
	EIF2B5	ENST00000481054.5	TSL:1	n.11C>T		non_coding_transcript_exon	Exon 1 of 15

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152210 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00 AC: 0 AN: 189634 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000210 AC: 3 AN: 1426738 Hom.: 0 Cov.: 30 AF XY: 0.00000283 AC XY: 2 AN XY: 705980

African (AFR) AF: 0.00 AC: 0 AN: 33276

American (AMR) AF: 0.0000269 AC: 1 AN: 37114

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25380

East Asian (EAS) AF: 0.00 AC: 0 AN: 38700

South Asian (SAS) AF: 0.00 AC: 0 AN: 81444

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49912

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5724

European-Non Finnish (NFE) AF: 0.00000182 AC: 2 AN: 1095958

Other (OTH) AF: 0.00 AC: 0 AN: 59230

GnomAD4 genome AF: 0.00000656 AC: 1 AN: 152328 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74496

African (AFR) AF: 0.0000241 AC: 1 AN: 41572

American (AMR) AF: 0.00 AC: 0 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000855 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	0.0073	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	0.44
DANN	Benign	0.93
DEOGEN2	Benign	0.051	T
Eigen	Benign	-1.9
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.017	N
LIST_S2	Benign	0.46	T
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.056	T
MetaSVM	Uncertain	0.018	D
MutationAssessor	Benign	0.0	N
PhyloP100		-1.6
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	0.10	N
REVEL	Benign	0.24
Sift	Benign	0.37	T
Sift4G	Benign	0.92	T
Polyphen		0.0	B
Vest4		0.16
MutPred		0.27		Gain of sheet (P = 0.0043)
MVP		0.30
MPC		0.28
ClinPred		0.092	T
GERP RS		-9.3
PromoterAI		0.050	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.026
gMVP		0.27
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs767998775; hg19: chr3-183853183;