12-10506741-G-C

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001357734.3(EIF2S3B):​c.839G>C​(p.Gly280Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,736 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: EIF2S3B NM_001357734.3 missense
• Clinical Significance: Not reported in ClinVar
• 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

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.852

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EIF2S3B	NM_001357734.3	c.839G>C	p.Gly280Ala	missense_variant	Exon 1 of 1	ENST00000538173.2	NP_001344663.1
EIF2S3B	NM_001357731.1	c.839G>C	p.Gly280Ala	missense_variant	Exon 1 of 2		NP_001344660.1
LOC105369657	XR_001749003.3	n.443-6140C>G		intron_variant	Intron 3 of 4
LOC105369657	XR_931355.4	n.443-6140C>G		intron_variant	Intron 3 of 5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EIF2S3B	ENST00000538173.2	c.839G>C	p.Gly280Ala	missense_variant	Exon 1 of 1	6	NM_001357734.3	ENSP00000445077.1
EIF2S3B	ENST00000322446.3	c.839G>C	p.Gly280Ala	missense_variant	Exon 1 of 2	1		ENSP00000323063.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461736 Hom.: 0 Cov.: 37 AF XY: 0.00000138 AC XY: 1 AN XY: 727174

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
BayesDel_addAF	Benign	-0.057	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	20
DANN	Benign	0.97
DEOGEN2	Benign	0.22	.;T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.64	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Benign	0.0046	T
MetaRNN	Pathogenic	0.85	D;D
MetaSVM	Benign	-0.59	T
PROVEAN	Pathogenic	-5.8	D;D
REVEL	Benign	0.22
Sift	Uncertain	0.0030	D;D
Sift4G	Uncertain	0.021	D;D
Vest4		0.58
MutPred		0.64		Loss of disorder (P = 0.1171);Loss of disorder (P = 0.1171);
MVP		0.56
MPC		0.36
ClinPred		1.0	D
GERP RS		0.37
Varity_R		0.70
gMVP		0.69

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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;