X-24057695-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_001415.4(EIF2S3):c.324T>A(p.Ser108Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 24)
• Consequence: EIF2S3 NM_001415.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 0.295

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, EIF2S3
• BP4: Computational evidence support a benign effect (MetaRNN=0.38057172).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EIF2S3	NM_001415.4	c.324T>A	p.Ser108Arg	missense_variant	4/12	ENST00000253039.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EIF2S3	ENST00000253039.9	c.324T>A	p.Ser108Arg	missense_variant	4/12	1	NM_001415.4	P1
EIF2S3	ENST00000423068.1	c.324T>A	p.Ser108Arg	missense_variant	4/5	2
EIF2S3	ENST00000487075.1	n.156+2017T>A		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 24

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

MEHMO syndrome Pathogenic:1 Uncertain:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 19, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute of Experimental Endocrinology, Slovak Academy of Sciences	Dec 12, 2016	missense in a gene with high constraint (z=3.81 in ExAc), not found in ExAc, in silico analysis - pathogenic, specific phenotype, no effect in functional study in yeast -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.71
BayesDel_addAF	Benign	-0.054	T
BayesDel_noAF	Benign	-0.32
Cadd	Benign	19
Dann	Uncertain	1.0
DEOGEN2	Benign	0.34	T
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.068	D
MetaRNN	Benign	0.38	T
MetaSVM	Benign	-0.35	T
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-3.0	D
REVEL	Uncertain	0.33
Sift	Uncertain	0.026	D
Sift4G	Benign	0.071	T
Polyphen		0.87	P
Vest4		0.37
MutPred		0.41		Loss of glycosylation at S108 (P = 0.0096);
MVP		0.66
MPC		1.3
ClinPred		0.99	D
GERP RS		-4.0
Varity_R		0.94
gMVP		0.96

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: rs1057515578; hg19: chrX-24075812;