rs377239918

Variant names:

• chrX-24055686-T-C
• rs377239918
• NM_001415.4:c.133+8T>C

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001415.4(EIF2S3):​c.133+8T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00111 in 1,206,576 control chromosomes in the GnomAD database, including 1 homozygotes. There are 413 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00056 (0 hom., 16 hem., cov: 23)
  • Exomes 𝑓: 0.0012 (1 hom. 397 hem.)
• Consequence: EIF2S3 NM_001415.4 splice_region, intron
• Scores: Splicing: ADA: 0.0005593
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.0190
• 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: 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: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant X-24055686-T-C is Benign according to our data. Variant chrX-24055686-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 210934.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 63 XL,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EIF2S3	NM_001415.4	c.133+8T>C		splice_region_variant, intron_variant	Intron 2 of 11	ENST00000253039.9	NP_001406.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EIF2S3	ENST00000253039.9	c.133+8T>C		splice_region_variant, intron_variant	Intron 2 of 11	1	NM_001415.4	ENSP00000253039.4
EIF2S3	ENST00000423068.1	c.130+8T>C		splice_region_variant, intron_variant	Intron 2 of 4	2		ENSP00000391383.1
EIF2S3	ENST00000487075.1	n.156+8T>C		splice_region_variant, intron_variant	Intron 2 of 2	5

Frequencies

GnomAD3 genomes AF: 0.000562 AC: 63 AN: 112003 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.000195

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000191

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000363

Gnomad FIN AF: 0.000828

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000921

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000646 AC: 118 AN: 182671 AF XY: 0.000655

Gnomad AFR exome AF: 0.000152

Gnomad AMR exome AF: 0.000184

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000250

Gnomad NFE exome AF: 0.00114

Gnomad OTH exome AF: 0.000665

GnomAD4 exome AF: 0.00116 AC: 1271 AN: 1094573 Hom.: 1 Cov.: 30 AF XY: 0.00110 AC XY: 397 AN XY: 360043

African (AFR) AF: 0.000152 AC: 4 AN: 26365

American (AMR) AF: 0.000200 AC: 7 AN: 35054

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19329

East Asian (EAS) AF: 0.00 AC: 0 AN: 30180

South Asian (SAS) AF: 0.000648 AC: 35 AN: 54034

European-Finnish (FIN) AF: 0.000518 AC: 21 AN: 40502

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4130

European-Non Finnish (NFE) AF: 0.00140 AC: 1174 AN: 839007

Other (OTH) AF: 0.000653 AC: 30 AN: 45972

GnomAD4 genome AF: 0.000562 AC: 63 AN: 112003 Hom.: 0 Cov.: 23 AF XY: 0.000468 AC XY: 16 AN XY: 34179

African (AFR) AF: 0.000195 AC: 6 AN: 30811

American (AMR) AF: 0.000191 AC: 2 AN: 10470

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2647

East Asian (EAS) AF: 0.00 AC: 0 AN: 3615

South Asian (SAS) AF: 0.000363 AC: 1 AN: 2758

European-Finnish (FIN) AF: 0.000828 AC: 5 AN: 6040

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 240

European-Non Finnish (NFE) AF: 0.000921 AC: 49 AN: 53229

Other (OTH) AF: 0.00 AC: 0 AN: 1511

Alfa AF: 0.000477 Hom.: 3

Bravo AF: 0.000536

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Dec 04, 2017

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

EIF2S3-related disorder Benign:1

Jan 30, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	1.5
DANN	Benign	0.75
PhyloP100		0.019
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00056
dbscSNV1_RF	Benign	0.0080
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: rs377239918; hg19: chrX-24073803;