rs886040857

Variant names:

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

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PS3 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 (★★). ClinVar reports functional evidence for this variant: "SCV000321299: functional study confirms effect on eIF2 function".

• 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: 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: Pathogenic. The variant received 14 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000321299: functional study confirms effect on eIF2 function
• 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.

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.1394_1397delTCAA	p.Ile465SerfsTer4	frameshift	Exon 12 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.1394_1397delTCAA	p.Ile465SerfsTer4	frameshift	Exon 12 of 12	ENSP00000253039.4	P41091
	EIF2S3	ENST00000864815.1		c.1391_1394delTCAA	p.Ile464SerfsTer4	frameshift	Exon 12 of 12	ENSP00000534874.1
	EIF2S3	ENST00000971837.1		c.1388_1391delTCAA	p.Ile463SerfsTer4	frameshift	Exon 12 of 12	ENSP00000641896.1

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

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	MEHMO syndrome (2)
2	-	-	not provided (2)

Computational scores

Source: dbNSFP v4.9

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;