rs886040857

Variant names:

• chrX-24076756-ACAAT-A
• rs886040857
• NM_001415.4:c.1394_1397delTCAA

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM2 PP5_Very_Strong

The NM_001415.4(EIF2S3):​c.1394_1397delTCAA​(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
• Publications: 10 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: Pathogenic. The variant received 10 ACMG points.

• 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 265789.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EIF2S3	NM_001415.4	c.1394_1397delTCAA	p.Ile465SerfsTer4	frameshift_variant	Exon 12 of 12	ENST00000253039.9	NP_001406.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EIF2S3	ENST00000253039.9	c.1394_1397delTCAA	p.Ile465SerfsTer4	frameshift_variant	Exon 12 of 12	1	NM_001415.4	ENSP00000253039.4
EIF2S3	ENST00000457332.1	n.151-584_151-581delTCAA		intron_variant	Intron 1 of 1	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

Sep 30, 2016

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

May 20, 2016

Clinical Genetics and Genomics, Karolinska University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

MEHMO syndrome Pathogenic:2

Jan 18, 2018

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Oct 07, 2016

Institute of Experimental Endocrinology, Slovak Academy of Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

found in 3 independent MEHMO patients, not found in ExAC, functional study confirms effect on eIF2 function -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.3
Mutation Taster		=1/199	disease causing (ClinVar)

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: rs886040857; hg19: chrX-24094873; COSMIC: COSV53406910; COSMIC: COSV53406910;