X-24055644-C-T

Position:

• chrX-24055644-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001415.4(EIF2S3):​c.99C>T​(p.His33His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.51 in 111,034 control chromosomes in the GnomAD database, including 12,202 homozygotes. There are 16,879 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.51 (12202 hom., 16879 hem., cov: 23)
  • Exomes 𝑓: 0.64 (160287 hom. 226881 hem.)
  • Failed GnomAD Quality Control
• Consequence: EIF2S3 NM_001415.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.0870

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant X-24055644-C-T is Benign according to our data. Variant chrX-24055644-C-T is described in ClinVar as [Benign]. Clinvar id is 128994.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-24055644-C-T is described in Lovd as [Benign]. Variant chrX-24055644-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.087 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.675 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EIF2S3	NM_001415.4	c.99C>T	p.His33His	synonymous_variant	2/12	ENST00000253039.9	NP_001406.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EIF2S3	ENST00000253039.9	c.99C>T	p.His33His	synonymous_variant	2/12	1	NM_001415.4	ENSP00000253039.4
EIF2S3	ENST00000423068.1	c.96C>T	p.His32His	synonymous_variant	2/5	2		ENSP00000391383.1
EIF2S3	ENST00000487075.1	n.122C>T		non_coding_transcript_exon_variant	2/3	5

Frequencies

GnomAD3 genomes AF: 0.510 AC: 56639 AN: 110981 Hom.: 12204 Cov.: 23 AF XY: 0.508 AC XY: 16870 AN XY: 33223

Gnomad AFR AF: 0.177

Gnomad AMI AF: 0.796

Gnomad AMR AF: 0.598

Gnomad ASJ AF: 0.623

Gnomad EAS AF: 0.362

Gnomad SAS AF: 0.222

Gnomad FIN AF: 0.693

Gnomad MID AF: 0.513

Gnomad NFE AF: 0.681

Gnomad OTH AF: 0.523

GnomAD3 exomes AF: 0.565 AC: 103230 AN: 182577 Hom.: 20814 AF XY: 0.554 AC XY: 37187 AN XY: 67143

Gnomad AFR exome AF: 0.164

Gnomad AMR exome AF: 0.620

Gnomad ASJ exome AF: 0.620

Gnomad EAS exome AF: 0.413

Gnomad SAS exome AF: 0.238

Gnomad FIN exome AF: 0.695

Gnomad NFE exome AF: 0.681

Gnomad OTH exome AF: 0.612

GnomAD4 exome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.640 AC: 702664 AN: 1097130 Hom.: 160287 Cov.: 35 AF XY: 0.625 AC XY: 226881 AN XY: 363002

Gnomad4 AFR exome AF: 0.162

Gnomad4 AMR exome AF: 0.619

Gnomad4 ASJ exome AF: 0.630

Gnomad4 EAS exome AF: 0.389

Gnomad4 SAS exome AF: 0.245

Gnomad4 FIN exome AF: 0.695

Gnomad4 NFE exome AF: 0.692

Gnomad4 OTH exome AF: 0.595

GnomAD4 genome AF: 0.510 AC: 56630 AN: 111034 Hom.: 12202 Cov.: 23 AF XY: 0.507 AC XY: 16879 AN XY: 33286

Gnomad4 AFR AF: 0.177

Gnomad4 AMR AF: 0.599

Gnomad4 ASJ AF: 0.623

Gnomad4 EAS AF: 0.361

Gnomad4 SAS AF: 0.222

Gnomad4 FIN AF: 0.693

Gnomad4 NFE AF: 0.681

Gnomad4 OTH AF: 0.518

Alfa AF: 0.592 Hom.: 6823

Bravo AF: 0.497

EpiCase AF: 0.677

EpiControl AF: 0.678

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 09, 2021	- -

MEHMO syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	4.2
DANN	Benign	0.80
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs36018672; hg19: chrX-24073761; COSMIC: COSV53406559;