12-53027788-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP2 BP4

The NM_001417.7(EIF4B):c.674G>A(p.Arg225Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000685 in 1,460,742 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: EIF4B NM_001417.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.14

Genes affected

EIF4B (HGNC:3285): (eukaryotic translation initiation factor 4B) Enables RNA binding activity. Predicted to be involved in eukaryotic translation initiation factor 4F complex assembly and formation of translation preinitiation complex. Located in cytosol. Biomarker of autism spectrum disorder and major depressive disorder. [provided by Alliance of Genome Resources, Apr 2022]

TNS2-AS1 (HGNC:27464): (TNS2 antisense RNA 1)

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PP2: Missense variant where missense usually causes diseases, EIF4B
• BP4: Computational evidence support a benign effect (MetaRNN=0.26578552).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EIF4B	NM_001417.7	c.674G>A	p.Arg225Gln	missense_variant	7/15	ENST00000262056.14
EIF4B	NM_001300821.3	c.674G>A	p.Arg225Gln	missense_variant	7/15
EIF4B	NM_001330654.2	c.557G>A	p.Arg186Gln	missense_variant	6/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EIF4B	ENST00000262056.14	c.674G>A	p.Arg225Gln	missense_variant	7/15	1	NM_001417.7	P4
TNS2-AS1	ENST00000552905.6	n.321-12845C>T		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD3 exomes AF: 0.00000810 AC: 2 AN: 246816 Hom.: 0 AF XY: 0.00000746 AC XY: 1 AN XY: 134126

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: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000181

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000685 AC: 10 AN: 1460742 Hom.: 0 Cov.: 59 AF XY: 0.00000550 AC XY: 4 AN XY: 726704

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000809

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

Alfa AF: 0.0000468 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 29, 2022

The c.674G>A (p.R225Q) alteration is located in exon 7 (coding exon 7) of the EIF4B gene. This alteration results from a G to A substitution at nucleotide position 674, causing the arginine (R) at amino acid position 225 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	0.0
Cadd	Pathogenic	29
Dann	Uncertain	1.0
DEOGEN2	Benign	0.36	T;.;.;.
Eigen	Benign	0.053
Eigen_PC	Benign	0.13
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.29	T;T;T;T
M_CAP	Uncertain	0.088	D
MetaRNN	Benign	0.27	T;T;T;T
MetaSVM	Uncertain	-0.036	T
MutationAssessor	Benign	1.5	L;.;.;.
MutationTaster	Benign	0.82	D;D;N
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-2.0	N;N;N;N
REVEL	Benign	0.24
Sift	Uncertain	0.014	D;D;D;T
Sift4G	Benign	0.12	T;T;T;T
Polyphen		0.80	P;P;.;.
Vest4		0.54
MutPred		0.34		Loss of MoRF binding (P = 0.0644);Loss of MoRF binding (P = 0.0644);.;.;
MVP		0.87
MPC		1.3
ClinPred		0.73	D
GERP RS		3.1
Varity_R		0.17
gMVP		0.62

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs1381944013; hg19: chr12-53421572; COSMIC: COSV50407637;