12-53019941-G-C

Variant names:

• chr12-53019941-G-C
• rs201365536
• NM_001417.7:c.392G>C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001417.7(EIF4B):​c.392G>C​(p.Ser131Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000343 in 1,612,602 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S131G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00029 (0 hom., cov: 30)
  • Exomes 𝑓: 0.00035 (0 hom.)
• Consequence: EIF4B NM_001417.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.74

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.13087097).
• BS2: High AC in GnomAd4 at 44 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EIF4B	NM_001417.7	c.392G>C	p.Ser131Thr	missense_variant	Exon 4 of 15	ENST00000262056.14	NP_001408.2
EIF4B	NM_001300821.3	c.392G>C	p.Ser131Thr	missense_variant	Exon 4 of 15		NP_001287750.1
EIF4B	NM_001330654.2	c.360+935G>C		intron_variant	Intron 3 of 13		NP_001317583.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EIF4B	ENST00000262056.14	c.392G>C	p.Ser131Thr	missense_variant	Exon 4 of 15	1	NM_001417.7	ENSP00000262056.9

Frequencies

GnomAD3 genomes AF: 0.000289 AC: 44 AN: 152160 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000456

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000266 AC: 66 AN: 248038 Hom.: 0 AF XY: 0.000282 AC XY: 38 AN XY: 134670

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000588

Gnomad ASJ exome AF: 0.0000994

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.000523

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.000349 AC: 509 AN: 1460442 Hom.: 0 Cov.: 30 AF XY: 0.000352 AC XY: 256 AN XY: 726560

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.0000903

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000243

Gnomad4 NFE exome AF: 0.000425

Gnomad4 OTH exome AF: 0.000232

GnomAD4 genome AF: 0.000289 AC: 44 AN: 152160 Hom.: 0 Cov.: 30 AF XY: 0.000256 AC XY: 19 AN XY: 74336

Gnomad4 AFR AF: 0.000145

Gnomad4 AMR AF: 0.000197

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000189

Gnomad4 NFE AF: 0.000456

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000422 Hom.: 0

Bravo AF: 0.000314

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000856 AC: 7

ExAC AF: 0.000306 AC: 37

EpiCase AF: 0.000927

EpiControl AF: 0.00107

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 02, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.392G>C (p.S131T) alteration is located in exon 4 (coding exon 4) of the EIF4B gene. This alteration results from a G to C substitution at nucleotide position 392, causing the serine (S) at amino acid position 131 to be replaced by a threonine (T). 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	0.13
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	21
DANN	Benign	0.87
DEOGEN2	Benign	0.12	T;T;.;.;.
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.32
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.79	T;T;T;T;T
M_CAP	Benign	0.047	D
MetaRNN	Benign	0.13	T;T;T;T;T
MetaSVM	Uncertain	-0.14	T
MutationAssessor	Benign	0.68	N;.;.;.;.
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-1.6	N;N;N;N;N
REVEL	Benign	0.29
Sift	Benign	0.18	T;T;T;T;T
Sift4G	Benign	0.20	T;T;T;T;T
Polyphen		0.0060	B;.;B;.;.
Vest4		0.19
MVP		0.85
MPC		0.80
ClinPred		0.040	T
GERP RS		2.7
Varity_R		0.14
gMVP		0.31

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: rs201365536; hg19: chr12-53413725; COSMIC: COSV50402395; COSMIC: COSV50402395;