chr2-99361611-A-T

Position:

• chr2-99361611-A-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The ENST00000289371.11(EIF5B):​c.710A>T​(p.Glu237Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00336 in 1,594,954 control chromosomes in the GnomAD database, including 30 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0032 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0034 (28 hom.)
• Consequence: EIF5B ENST00000289371.11 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 7.84

Genes affected

EIF5B (HGNC:30793): (eukaryotic translation initiation factor 5B) Accurate initiation of translation in eukaryotes is complex and requires many factors, some of which are composed of multiple subunits. The process is simpler in prokaryotes which have only three initiation factors (IF1, IF2, IF3). Two of these factors are conserved in eukaryotes: the homolog of IF1 is eIF1A and the homolog of IF2 is eIF5B. This gene encodes eIF5B. Factors eIF1A and eIF5B interact on the ribosome along with other initiation factors and GTP to position the initiation methionine tRNA on the start codon of the mRNA so that translation initiates accurately. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007859021).
• BP6: Variant 2-99361611-A-T is Benign according to our data. Variant chr2-99361611-A-T is described in ClinVar as [Likely_benign]. Clinvar id is 782085.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 494 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EIF5B	NM_015904.4	c.710A>T	p.Glu237Val	missense_variant	4/24	ENST00000289371.11	NP_056988.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EIF5B	ENST00000289371.11	c.710A>T	p.Glu237Val	missense_variant	4/24	1	NM_015904.4	ENSP00000289371	P1

Frequencies

GnomAD3 genomes AF: 0.00325 AC: 494 AN: 152200 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000868

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000981

Gnomad ASJ AF: 0.00778

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00245

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00564

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00328 AC: 755 AN: 230318 Hom.: 2 AF XY: 0.00300 AC XY: 376 AN XY: 125254

Gnomad AFR exome AF: 0.000266

Gnomad AMR exome AF: 0.000978

Gnomad ASJ exome AF: 0.00945

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000230

Gnomad FIN exome AF: 0.00227

Gnomad NFE exome AF: 0.00523

Gnomad OTH exome AF: 0.00366

GnomAD4 exome AF: 0.00337 AC: 4867 AN: 1442636 Hom.: 28 Cov.: 31 AF XY: 0.00339 AC XY: 2432 AN XY: 717074

Gnomad4 AFR exome AF: 0.000566

Gnomad4 AMR exome AF: 0.000816

Gnomad4 ASJ exome AF: 0.00946

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.000346

Gnomad4 FIN exome AF: 0.00324

Gnomad4 NFE exome AF: 0.00375

Gnomad4 OTH exome AF: 0.00366

GnomAD4 genome AF: 0.00324 AC: 494 AN: 152318 Hom.: 2 Cov.: 32 AF XY: 0.00287 AC XY: 214 AN XY: 74494

Gnomad4 AFR AF: 0.000866

Gnomad4 AMR AF: 0.000980

Gnomad4 ASJ AF: 0.00778

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00245

Gnomad4 NFE AF: 0.00564

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00520 Hom.: 6

Bravo AF: 0.00284

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00337 AC: 13

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00478 AC: 39

ExAC AF: 0.00324 AC: 391

EpiCase AF: 0.00464

EpiControl AF: 0.00362

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	EIF5B: BS2 -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.13
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.63	D;T
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.0079	T;T
MetaSVM	Benign	-0.68	T
MutationAssessor	Uncertain	2.2	M;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-3.0	D;.
REVEL	Benign	0.28
Sift	Pathogenic	0.0	D;.
Sift4G	Benign	0.11	T;T
Polyphen		1.0	D;.
Vest4		0.50
MVP		0.55
MPC		0.18
ClinPred		0.050	T
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.34
gMVP		0.34

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

LitVar

Other links and lift over

dbSNP: rs201583340; hg19: chr2-99978074; COSMIC: COSV56812575;