12-53027854-G-A

Variant names:

• chr12-53027854-G-A
• rs748695673
• NM_001417.7:c.740G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001417.7(EIF4B):​c.740G>A​(p.Arg247Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000836 in 1,614,120 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: 𝑓 0.00011 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000081 (0 hom.)
• Consequence: EIF4B NM_001417.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.30

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

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07935384).
• BS2: High AC in GnomAd4 at 16 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EIF4B	NM_001417.7	c.740G>A	p.Arg247Gln	missense_variant	Exon 7 of 15	ENST00000262056.14	NP_001408.2
EIF4B	NM_001300821.3	c.740G>A	p.Arg247Gln	missense_variant	Exon 7 of 15		NP_001287750.1
EIF4B	NM_001330654.2	c.623G>A	p.Arg208Gln	missense_variant	Exon 6 of 14		NP_001317583.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EIF4B	ENST00000262056.14	c.740G>A	p.Arg247Gln	missense_variant	Exon 7 of 15	1	NM_001417.7	ENSP00000262056.9

Frequencies

GnomAD3 genomes AF: 0.000105 AC: 16 AN: 152270 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000847

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000206 AC: 51 AN: 247334 AF XY: 0.000164

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000492

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00121

Gnomad NFE exome AF: 0.0000360

Gnomad OTH exome AF: 0.000661

GnomAD4 exome AF: 0.0000814 AC: 119 AN: 1461850 Hom.: 0 Cov.: 58 AF XY: 0.0000756 AC XY: 55 AN XY: 727228

Gnomad4 AFR exome AF: 0.00 AC: 0 AN: 33476

Gnomad4 AMR exome AF: 0.000470 AC: 21 AN: 44724

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26136

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39700

Gnomad4 SAS exome AF: 0.00 AC: 0 AN: 86254

Gnomad4 FIN exome AF: 0.00124 AC: 66 AN: 53416

Gnomad4 NFE exome AF: 0.0000207 AC: 23 AN: 1111998

Gnomad4 Remaining exome AF: 0.000149 AC: 9 AN: 60396

GnomAD4 genome AF: 0.000105 AC: 16 AN: 152270 Hom.: 0 Cov.: 34 AF XY: 0.000108 AC XY: 8 AN XY: 74392

Gnomad4 AFR AF: 0.00 AC: 0 AN: 0

Gnomad4 AMR AF: 0.000327 AC: 0.000327139 AN: 0.000327139

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.000847 AC: 0.00084682 AN: 0.00084682

Gnomad4 NFE AF: 0.0000294 AC: 0.0000293884 AN: 0.0000293884

Gnomad4 OTH AF: 0.00 AC: 0 AN: 0

Alfa AF: 0.0000752 Hom.: 0

Bravo AF: 0.0000831

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.0000993 AC: 12

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 30, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.740G>A (p.R247Q) 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 740, causing the arginine (R) at amino acid position 247 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	0.78
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.25
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.40	T;.;.;.
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.0060
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.84	T;T;T;T
M_CAP	Benign	0.0094	T
MetaRNN	Benign	0.079	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.0	M;.;.;.
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-1.3	N;N;N;N
REVEL	Benign	0.20
Sift	Benign	0.098	T;T;T;D
Sift4G	Benign	0.062	T;T;T;T
Polyphen		0.052	B;B;.;.
Vest4		0.47
MutPred		0.35		Loss of MoRF binding (P = 0.0259);Loss of MoRF binding (P = 0.0259);.;.;
MVP		0.84
MPC		1.3
ClinPred		0.092	T
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.074
gMVP		0.79
Mutation Taster		=80/20	polymorphism

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: rs748695673; hg19: chr12-53421638;