rs886040857

Positions:

• chrX-24076756-ACAAT-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_Moderate PM2 PP5_Very_Strong

The NM_001415.4(EIF2S3):​c.1394_1397del​(p.Ile465SerfsTer4) variant causes a frameshift 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 Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: EIF2S3 NM_001415.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 8.34

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 Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0197 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-24076756-ACAAT-A is Pathogenic according to our data. Variant chrX-24076756-ACAAT-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 265789.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-24076756-ACAAT-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EIF2S3	NM_001415.4	c.1394_1397del	p.Ile465SerfsTer4	frameshift_variant	12/12	ENST00000253039.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EIF2S3	ENST00000253039.9	c.1394_1397del	p.Ile465SerfsTer4	frameshift_variant	12/12	1	NM_001415.4	P1
EIF2S3	ENST00000457332.1	n.151-584_151-581del		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes Cov.: 22

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 30, 2016	The c.1394_1397delTCAA variant in the EIF2S3 gene has been reported previously in a family segregating a form of syndromic X-linked intellectual disability characterized by neonatal hypoglycemia, severe microcephaly, developmental delay, micropenis, epileptic seizures and early death (Moortgat et al., 2016). In this family, the c.1394_1397delTCAA variant was present in three obligate carrier female relatives and absent in three healthy male relatives, however, no affected male relatives were available for testing (Moorgat et al., 2016). The c.1394_1397delTCAA variant causes a frameshift starting with codon Isoleucine 465, changes this amino acid to a Serine residue, and creates a premature Stop codon at position 4 of the new reading frame, denoted p.Ile465SerfsX4. This variant is predicted to cause loss of normal protein function through protein truncation. The c.1394_1397delTCAA variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Therefore, we interpret c.1394_1397delTCAA variant as a likely pathogenic variant. -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	May 20, 2016	- -

MEHMO syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Experimental Endocrinology, Slovak Academy of Sciences	Oct 07, 2016	found in 3 independent MEHMO patients, not found in ExAC, functional study confirms effect on eIF2 function -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 18, 2018	- -

Computational scores

Source: dbNSFP v4.3

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: rs886040857; hg19: chrX-24094873;