12-53028018-A-G

Variant names:

• chr12-53028018-A-G
• rs755086357
• NM_001417.7:c.809A>G

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.809A>G​(p.Tyr270Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000807 in 1,610,792 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 0.000020 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000069 (0 hom.)
• Consequence: EIF4B NM_001417.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.10
• Publications: 0 publications found

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=0.25342962).
• BS2: High AC in GnomAdExome4 at 10 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001417.7. 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
	EIF4B	NM_001417.7	MANE Select	c.809A>G	p.Tyr270Cys	missense	Exon 8 of 15	NP_001408.2	P23588-1
	EIF4B	NM_001300821.3		c.809A>G	p.Tyr270Cys	missense	Exon 8 of 15	NP_001287750.1	E7EX17
	EIF4B	NM_001330654.2		c.692A>G	p.Tyr231Cys	missense	Exon 7 of 14	NP_001317583.1	P23588-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EIF4B	ENST00000262056.14	TSL:1 MANE Select	c.809A>G	p.Tyr270Cys	missense	Exon 8 of 15	ENSP00000262056.9	P23588-1
	EIF4B	ENST00000961691.1		c.809A>G	p.Tyr270Cys	missense	Exon 8 of 15	ENSP00000631750.1
	EIF4B	ENST00000961687.1		c.809A>G	p.Tyr270Cys	missense	Exon 8 of 15	ENSP00000631746.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152050 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

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: 0.00000809 AC: 2 AN: 247226 AF XY: 0.0000149

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: 0.00000892

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000686 AC: 10 AN: 1458742 Hom.: 0 Cov.: 33 AF XY: 0.00000827 AC XY: 6 AN XY: 725246

African (AFR) AF: 0.00 AC: 0 AN: 33396

American (AMR) AF: 0.00 AC: 0 AN: 44466

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25974

East Asian (EAS) AF: 0.00 AC: 0 AN: 39644

South Asian (SAS) AF: 0.0000233 AC: 2 AN: 85894

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53328

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.00000631 AC: 7 AN: 1110060

Other (OTH) AF: 0.0000166 AC: 1 AN: 60228

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152050 Hom.: 0 Cov.: 31 AF XY: 0.0000404 AC XY: 3 AN XY: 74252

African (AFR) AF: 0.0000483 AC: 2 AN: 41386

American (AMR) AF: 0.00 AC: 0 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10582

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

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

Other (OTH) AF: 0.00 AC: 0 AN: 2084

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.61
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.61	D
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.25	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.9	L
PhyloP100		1.1
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-4.6	D
REVEL	Benign	0.17
Sift	Benign	0.091	T
Sift4G	Benign	0.11	T
Polyphen		0.99	D
Vest4		0.56
MutPred		0.31		Gain of catalytic residue at R268 (P = 0.0107)
MVP		0.47
MPC		2.0
ClinPred		0.88	D
GERP RS		3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.19
gMVP		0.67
Mutation Taster		=74/26	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs755086357; hg19: chr12-53421802;