X-24057745-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2 BP4_Strong BP6 BA1

The NM_001415.4(EIF2S3):c.374A>G(p.Lys125Arg) variant causes a missense change. The variant allele was found at a frequency of 0.148 in 1,205,280 control chromosomes in the GnomAD database, including 9,523 homozygotes. There are 60,594 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.12 (703 hom., 3868 hem., cov: 24)
  • Exomes 𝑓: 0.15 (8820 hom. 56726 hem.)
• Consequence: EIF2S3 NM_001415.4 missense
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 7.03

Genes affected

EIF2S3 (HGNC:3267): (eukaryotic translation initiation factor 2 subunit gamma) The protein encoded by this gene is the largest subunit of a heterotrimeric GTP-binding protein involved in the recruitment of methionyl-tRNA(i) to the 40 S ribosomal subunit. [provided by RefSeq, Jan 2010]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• PP2: Missense variant where missense usually causes diseases, EIF2S3
• BP4: Computational evidence support a benign effect (MetaRNN=0.0017216206).
• BP6: Variant X-24057745-A-G is Benign according to our data. Variant chrX-24057745-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 128993.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.22 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EIF2S3	NM_001415.4	c.374A>G	p.Lys125Arg	missense_variant	4/12	ENST00000253039.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EIF2S3	ENST00000253039.9	c.374A>G	p.Lys125Arg	missense_variant	4/12	1	NM_001415.4	P1
EIF2S3	ENST00000423068.1	c.374A>G	p.Lys125Arg	missense_variant	4/5	2
EIF2S3	ENST00000487075.1	n.156+2067A>G		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.117 AC: 13120 AN: 111859 Hom.: 701 Cov.: 24 AF XY: 0.113 AC XY: 3862 AN XY: 34027

Gnomad AFR AF: 0.0362

Gnomad AMI AF: 0.0957

Gnomad AMR AF: 0.138

Gnomad ASJ AF: 0.204

Gnomad EAS AF: 0.00832

Gnomad SAS AF: 0.234

Gnomad FIN AF: 0.119

Gnomad MID AF: 0.189

Gnomad NFE AF: 0.157

Gnomad OTH AF: 0.135

GnomAD3 exomes AF: 0.146 AC: 25860 AN: 177160 Hom.: 1347 AF XY: 0.156 AC XY: 9788 AN XY: 62562

Gnomad AFR exome AF: 0.0348

Gnomad AMR exome AF: 0.172

Gnomad ASJ exome AF: 0.197

Gnomad EAS exome AF: 0.00387

Gnomad SAS exome AF: 0.238

Gnomad FIN exome AF: 0.130

Gnomad NFE exome AF: 0.157

Gnomad OTH exome AF: 0.160

GnomAD4 exome AF: 0.151 AC: 165458 AN: 1093368 Hom.: 8820 Cov.: 30 AF XY: 0.158 AC XY: 56726 AN XY: 359640

Gnomad4 AFR exome AF: 0.0368

Gnomad4 AMR exome AF: 0.169

Gnomad4 ASJ exome AF: 0.193

Gnomad4 EAS exome AF: 0.00199

Gnomad4 SAS exome AF: 0.244

Gnomad4 FIN exome AF: 0.133

Gnomad4 NFE exome AF: 0.153

Gnomad4 OTH exome AF: 0.144

GnomAD4 genome AF: 0.117 AC: 13127 AN: 111912 Hom.: 703 Cov.: 24 AF XY: 0.113 AC XY: 3868 AN XY: 34090

Gnomad4 AFR AF: 0.0362

Gnomad4 AMR AF: 0.138

Gnomad4 ASJ AF: 0.204

Gnomad4 EAS AF: 0.00807

Gnomad4 SAS AF: 0.235

Gnomad4 FIN AF: 0.119

Gnomad4 NFE AF: 0.157

Gnomad4 OTH AF: 0.139

Alfa AF: 0.126 Hom.: 1441

Bravo AF: 0.113

TwinsUK AF: 0.155 AC: 575

ALSPAC AF: 0.152 AC: 440

ESP6500AA AF: 0.0381 AC: 146

ESP6500EA AF: 0.160 AC: 1077

ExAC AF: 0.148 AC: 18023

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

not specified Benign:1

Likely benign, no assertion criteria provided

clinical testing

Genetic Services Laboratory, University of Chicago

-

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.46
Cadd	Benign	18
Dann	Uncertain	0.99
DEOGEN2	Benign	0.055	T
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.87	D
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.00055	P
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-0.21	N
REVEL	Benign	0.14
Sift	Benign	0.48	T
Sift4G	Benign	0.43	T
Polyphen		0.0	B
Vest4		0.071
MPC		1.4
ClinPred		0.028	T
GERP RS		3.9
Varity_R		0.22
gMVP		0.79

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: rs16997659; hg19: chrX-24075862; COSMIC: COSV53405694;