12-10506741-G-A

Variant names:

• chr12-10506741-G-A
• rs199779592
• NM_001357734.3:c.839G>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_001357734.3(EIF2S3B):​c.839G>A​(p.Gly280Asp) variant causes a missense change. The variant allele was found at a frequency of 0.00546 in 1,614,002 control chromosomes in the GnomAD database, including 30 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0035 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0057 (28 hom.)
• Consequence: EIF2S3B NM_001357734.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 5.01

Genes affected

EIF2S3B (HGNC:43863): (eukaryotic translation initiation factor 2 subunit gamma B) Predicted to enable translation initiation factor activity. Predicted to contribute to tRNA binding activity. Predicted to be involved in formation of translation preinitiation complex and positive regulation of translational fidelity. Predicted to be part of eukaryotic translation initiation factor 2 complex. Predicted to be active in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

LOC105369657 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.061276555).
• BP6: Variant 12-10506741-G-A is Benign according to our data. Variant chr12-10506741-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2642701.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EIF2S3B	NM_001357734.3	c.839G>A	p.Gly280Asp	missense_variant	Exon 1 of 1	ENST00000538173.2	NP_001344663.1
EIF2S3B	NM_001357731.1	c.839G>A	p.Gly280Asp	missense_variant	Exon 1 of 2		NP_001344660.1
LOC105369657	XR_001749003.3	n.443-6140C>T		intron_variant	Intron 3 of 4
LOC105369657	XR_931355.4	n.443-6140C>T		intron_variant	Intron 3 of 5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EIF2S3B	ENST00000538173.2	c.839G>A	p.Gly280Asp	missense_variant	Exon 1 of 1	6	NM_001357734.3	ENSP00000445077.1
EIF2S3B	ENST00000322446.3	c.839G>A	p.Gly280Asp	missense_variant	Exon 1 of 2	1		ENSP00000323063.3

Frequencies

GnomAD3 genomes AF: 0.00346 AC: 526 AN: 152168 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00116

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00314

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00594

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00341 AC: 857 AN: 251466 AF XY: 0.00348

Gnomad AFR exome AF: 0.00105

Gnomad AMR exome AF: 0.00130

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00282

Gnomad NFE exome AF: 0.00626

Gnomad OTH exome AF: 0.00359

GnomAD4 exome AF: 0.00567 AC: 8293 AN: 1461716 Hom.: 28 Cov.: 37 AF XY: 0.00549 AC XY: 3993 AN XY: 727170

Gnomad4 AFR exome AF: 0.000806 AC: 27 AN: 33480

Gnomad4 AMR exome AF: 0.00152 AC: 68 AN: 44724

Gnomad4 ASJ exome AF: 0.000153 AC: 4 AN: 26132

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

Gnomad4 SAS exome AF: 0.0000116 AC: 1 AN: 86254

Gnomad4 FIN exome AF: 0.00331 AC: 177 AN: 53420

Gnomad4 NFE exome AF: 0.00698 AC: 7762 AN: 1111846

Gnomad4 Remaining exome AF: 0.00417 AC: 252 AN: 60392

GnomAD4 genome AF: 0.00345 AC: 526 AN: 152286 Hom.: 2 Cov.: 32 AF XY: 0.00293 AC XY: 218 AN XY: 74478

Gnomad4 AFR AF: 0.00116 AC: 0.00115529 AN: 0.00115529

Gnomad4 AMR AF: 0.00314 AC: 0.00313767 AN: 0.00313767

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: 0.00189 AC: 0.00188501 AN: 0.00188501

Gnomad4 NFE AF: 0.00594 AC: 0.00593908 AN: 0.00593908

Gnomad4 OTH AF: 0.00284 AC: 0.00283554 AN: 0.00283554

Alfa AF: 0.00115 Hom.: 0

Bravo AF: 0.00362

TwinsUK AF: 0.00620 AC: 23

ALSPAC AF: 0.00467 AC: 18

ExAC AF: 0.00329 AC: 399

EpiCase AF: 0.00573

EpiControl AF: 0.00569

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Apr 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

EIF2S3B: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.21
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	.;T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.39
FATHMM_MKL	Benign	0.36	N
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Benign	0.0043	T
MetaRNN	Benign	0.061	T;T
MetaSVM	Benign	-0.60	T
PROVEAN	Pathogenic	-6.8	D;D
REVEL	Uncertain	0.30
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Vest4		0.75
MVP		0.55
MPC		0.50
ClinPred		0.11	T
GERP RS		0.37
Varity_R		0.82
gMVP		0.86
Mutation Taster		=64/36	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: rs199779592; hg19: chr12-10659340;