12-53016553-A-G

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 1P and 8B. PP2 BP4_Strong BS2

The NM_001417.7(EIF4B):c.94A>G(p.Thr32Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000387 in 1,613,382 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00039 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00039 (2 hom.)
• Consequence: EIF4B NM_001417.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.32

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 Benign. Variant got -7 ACMG points.

• PP2: Missense variant where missense usually causes diseases, EIF4B
• BP4: Computational evidence support a benign effect (MetaRNN=0.008408636).
• BS2: High AC in GnomAd at 60 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EIF4B	NM_001417.7	c.94A>G	p.Thr32Ala	missense_variant	2/15	ENST00000262056.14
EIF4B	NM_001300821.3	c.94A>G	p.Thr32Ala	missense_variant	2/15
EIF4B	NM_001330654.2	c.94A>G	p.Thr32Ala	missense_variant	2/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EIF4B	ENST00000262056.14	c.94A>G	p.Thr32Ala	missense_variant	2/15	1	NM_001417.7	P4
TNS2-AS1	ENST00000552905.6	n.321-1610T>C		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.000394 AC: 60 AN: 152228 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00950

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000323

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000555 AC: 138 AN: 248586 Hom.: 0 AF XY: 0.000519 AC XY: 70 AN XY: 134886

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.000321

Gnomad ASJ exome AF: 0.00907

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000266

Gnomad OTH exome AF: 0.000828

GnomAD4 exome AF: 0.000386 AC: 564 AN: 1461036 Hom.: 2 Cov.: 30 AF XY: 0.000374 AC XY: 272 AN XY: 726814

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000292

Gnomad4 ASJ exome AF: 0.00931

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000230

Gnomad4 OTH exome AF: 0.000746

GnomAD4 genome AF: 0.000394 AC: 60 AN: 152346 Hom.: 0 Cov.: 33 AF XY: 0.000403 AC XY: 30 AN XY: 74510

Gnomad4 AFR AF: 0.0000240

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00950

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000323

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.000666 Hom.: 0

Bravo AF: 0.000450

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000367 AC: 3

ExAC AF: 0.000373 AC: 45

EpiCase AF: 0.00104

EpiControl AF: 0.000356

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

Jul 14, 2022

The c.94A>G (p.T32A) alteration is located in exon 2 (coding exon 2) of the EIF4B gene. This alteration results from a A to G substitution at nucleotide position 94, causing the threonine (T) at amino acid position 32 to be replaced by an alanine (A). 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	Benign	0.090
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.12
Cadd	Benign	21
Dann	Benign	0.73
DEOGEN2	Benign	0.23	T;.;.;.;.
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.37
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.70	T;T;T;T;T
M_CAP	Benign	0.063	D
MetaRNN	Benign	0.0084	T;T;T;T;T
MetaSVM	Uncertain	-0.13	T
MutationAssessor	Uncertain	2.1	M;.;M;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.8	N;N;N;N;N
REVEL	Benign	0.29
Sift	Benign	0.13	T;T;T;T;T
Sift4G	Benign	0.23	T;T;T;T;T
Polyphen		0.077	B;B;.;.;.
Vest4		0.28
MVP		0.89
MPC		1.1
ClinPred		0.053	T
GERP RS		3.5
Varity_R		0.063
gMVP		0.27

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: rs201924839; hg19: chr12-53410337;