NM_001415.4:c.281C>G

Variant names:

• chrX-24057652-C-G
• NM_001415.4:c.281C>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP2

The NM_001415.4(EIF2S3):​c.281C>G​(p.Pro94Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P94T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 24)
• Consequence: EIF2S3 NM_001415.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.48
• Publications: 0 publications found

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]

EIF2S3 Gene-Disease associations (from GenCC):

• MEHMO syndrome

  Inheritance: XL, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae), ClinGen, Genomics England PanelApp
• diabetes mellitus

  Inheritance: XL Classification: STRONG Submitted by: Genomics England PanelApp

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 7 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Gene score misZ: 3.6078 (above the threshold of 3.09). Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to MEHMO syndrome, diabetes mellitus.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001415.4. 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
	EIF2S3	NM_001415.4	MANE Select	c.281C>G	p.Pro94Arg	missense	Exon 4 of 12	NP_001406.1	P41091

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EIF2S3	ENST00000253039.9	TSL:1 MANE Select	c.281C>G	p.Pro94Arg	missense	Exon 4 of 12	ENSP00000253039.4	P41091
	EIF2S3	ENST00000864815.1		c.281C>G	p.Pro94Arg	missense	Exon 4 of 12	ENSP00000534874.1
	EIF2S3	ENST00000971837.1		c.281C>G	p.Pro94Arg	missense	Exon 4 of 12	ENSP00000641896.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 24

ClinVar

ClinVar submissions

Significance: Uncertain significance

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	Benign	0.13
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.010
CADD	Uncertain	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.38	T
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.16	D
MetaRNN	Uncertain	0.70	D
MetaSVM	Uncertain	-0.13	T
PhyloP100		7.5
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-4.1	D
REVEL	Uncertain	0.48
Sift	Uncertain	0.014	D
Sift4G	Uncertain	0.017	D
Polyphen		0.27	B
Vest4		0.63
MutPred		0.49		Gain of catalytic residue at P94 (P = 0.0262)
MVP		0.86
MPC		1.2
ClinPred		0.99	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.78
gMVP		0.93
Mutation Taster		=16/84	disease causing

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

hg19: chrX-24075769;