X-24055032-A-G

Variant names:

• chrX-24055032-A-G
• rs1372768032
• NM_001415.4:c.64A>G

Variant summary

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

The NM_001415.4(EIF2S3):​c.64A>G​(p.Thr22Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000993 in 1,208,283 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000018 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 0.0000091 (0 hom. 2 hem.)
• Consequence: EIF2S3 NM_001415.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.29

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.14821374).
• BS2: High Hemizygotes in GnomAdExome4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EIF2S3	NM_001415.4	c.64A>G	p.Thr22Ala	missense_variant	Exon 1 of 12	ENST00000253039.9	NP_001406.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EIF2S3	ENST00000253039.9	c.64A>G	p.Thr22Ala	missense_variant	Exon 1 of 12	1	NM_001415.4	ENSP00000253039.4
EIF2S3	ENST00000423068.1	c.61A>G	p.Thr21Ala	missense_variant	Exon 1 of 5	2		ENSP00000391383.1
EIF2S3	ENST00000487075.1	n.87A>G		non_coding_transcript_exon_variant	Exon 1 of 3	5

Frequencies

GnomAD3 genomes AF: 0.0000181 AC: 2 AN: 110769 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 33045

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000379

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000911 AC: 10 AN: 1097514 Hom.: 0 Cov.: 30 AF XY: 0.00000551 AC XY: 2 AN XY: 363014

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000107

Gnomad4 OTH exome AF: 0.0000217

GnomAD4 genome AF: 0.0000181 AC: 2 AN: 110769 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 33045

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000379

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Feb 28, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	17
DANN	Benign	0.97
DEOGEN2	Benign	0.10	T
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.080	D
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-0.91	T
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.98	N
REVEL	Benign	0.056
Sift	Benign	0.24	T
Sift4G	Benign	0.35	T
Polyphen		0.0010	B
Vest4		0.32
MutPred		0.22		Loss of glycosylation at T22 (P = 0.0581);
MVP		0.75
MPC		0.71
ClinPred		0.58	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.25
gMVP		0.67

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: rs1372768032; hg19: chrX-24073149;