chr12-10506741-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
• Publications: 0 publications found

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 VariationId is 2642701.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd4 at 2 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001357734.3. 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
	EIF2S3B	NM_001357734.3	MANE Select	c.839G>A	p.Gly280Asp	missense	Exon 1 of 1	NP_001344663.1
	EIF2S3B	NM_001357731.1		c.839G>A	p.Gly280Asp	missense	Exon 1 of 2	NP_001344660.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EIF2S3B	ENST00000538173.2	TSL:6 MANE Select	c.839G>A	p.Gly280Asp	missense	Exon 1 of 1	ENSP00000445077.1
	EIF2S3B	ENST00000322446.3	TSL:1	c.839G>A	p.Gly280Asp	missense	Exon 1 of 2	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

African (AFR) AF: 0.000806 AC: 27 AN: 33480

American (AMR) AF: 0.00152 AC: 68 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000153 AC: 4 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86254

European-Finnish (FIN) AF: 0.00331 AC: 177 AN: 53420

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.00698 AC: 7762 AN: 1111846

Other (OTH) 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

African (AFR) AF: 0.00116 AC: 48 AN: 41548

American (AMR) AF: 0.00314 AC: 48 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00189 AC: 20 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00594 AC: 404 AN: 68024

Other (OTH) AF: 0.00284 AC: 6 AN: 2116

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

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Benign	0.0043	T
MetaRNN	Benign	0.061	T
MetaSVM	Benign	-0.60	T
PhyloP100		5.0
PROVEAN	Pathogenic	-6.8	D
REVEL	Uncertain	0.30
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	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

Other links and lift over

dbSNP: rs199779592; hg19: chr12-10659340;