rs377239918

chrX-24055686-T-C

Variant summary

Our verdict is Benign. Variant got -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

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 Benign. Variant got -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 Hemizygotes in GnomAd at 16 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EIF2S3	NM_001415.4	c.133+8T>C		splice_region_variant, intron_variant		ENST00000253039.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EIF2S3	ENST00000253039.9	c.133+8T>C		splice_region_variant, intron_variant		1	NM_001415.4	P1
EIF2S3	ENST00000423068.1	c.131+8T>C		splice_region_variant, intron_variant		2
EIF2S3	ENST00000487075.1	n.156+8T>C		splice_region_variant, intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.000562 AC: 63 AN: 112003 Hom.: 0 Cov.: 23 AF XY: 0.000468 AC XY: 16 AN XY: 34179

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

GnomAD3 exomes AF: 0.000646 AC: 118 AN: 182671 Hom.: 0 AF XY: 0.000655 AC XY: 44 AN XY: 67139

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 SAS exome AF: 0.000579

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

Gnomad4 AFR exome AF: 0.000152

Gnomad4 AMR exome AF: 0.000200

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000648

Gnomad4 FIN exome AF: 0.000518

Gnomad4 NFE exome AF: 0.00140

Gnomad4 OTH exome AF: 0.000653

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

Gnomad4 AFR AF: 0.000195

Gnomad4 AMR AF: 0.000191

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000363

Gnomad4 FIN AF: 0.000828

Gnomad4 NFE AF: 0.000921

Gnomad4 OTH AF: 0.00

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

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Dec 04, 2017

- -

EIF2S3-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 30, 2024

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
Cadd	Benign	1.5
Dann	Benign	0.75

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

Publications

LitVar

Other links and lift over

dbSNP: rs377239918; hg19: chrX-24073803;