X-24057695-T-A

Variant names:

• chrX-24057695-T-A
• rs1057515578
• NM_001415.4:c.324T>A

Variant summary

Our verdict is Uncertain significance. The variant received 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
• Publications: 6 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: Labcorp Genetics (formerly Invitae), G2P, Orphanet, ClinGen, Genomics England PanelApp
• diabetes mellitus

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.38057172).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EIF2S3	NM_001415.4	MANE Select	c.324T>A	p.Ser108Arg	missense	Exon 4 of 12	NP_001406.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EIF2S3	ENST00000253039.9	TSL:1 MANE Select	c.324T>A	p.Ser108Arg	missense	Exon 4 of 12	ENSP00000253039.4
	EIF2S3	ENST00000423068.1	TSL:2	c.321T>A	p.Ser107Arg	missense	Exon 4 of 5	ENSP00000391383.1
	EIF2S3	ENST00000487075.1	TSL:5	n.156+2017T>A		intron	N/A

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

Dec 12, 2016

Institute of Experimental Endocrinology, Slovak Academy of Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jan 19, 2018

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		0.29
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
Mutation Taster		=14/86	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

dbSNP: rs1057515578; hg19: chrX-24075812;