NM_001415.4:c.99C>T

Variant names:

• chrX-24055644-C-T
• rs36018672
• NM_001415.4:c.99C>T

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 14 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: Benign. The variant received -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 VariationId is 128994.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.

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.99C>T	p.His33His	synonymous	Exon 2 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.99C>T	p.His33His	synonymous	Exon 2 of 12	ENSP00000253039.4	P41091
	EIF2S3	ENST00000864815.1		c.99C>T	p.His33His	synonymous	Exon 2 of 12	ENSP00000534874.1
	EIF2S3	ENST00000971837.1		c.99C>T	p.His33His	synonymous	Exon 2 of 12	ENSP00000641896.1

Frequencies

GnomAD3 genomes AF: 0.510 AC: 56639 AN: 110981 Hom.: 12204 Cov.: 23

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

GnomAD2 exomes AF: 0.565 AC: 103230 AN: 182577 AF XY: 0.554

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 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

African (AFR) AF: 0.162 AC: 4267 AN: 26392

American (AMR) AF: 0.619 AC: 21742 AN: 35129

Ashkenazi Jewish (ASJ) AF: 0.630 AC: 12201 AN: 19361

East Asian (EAS) AF: 0.389 AC: 11744 AN: 30179

South Asian (SAS) AF: 0.245 AC: 13261 AN: 54107

European-Finnish (FIN) AF: 0.695 AC: 28115 AN: 40481

Middle Eastern (MID) AF: 0.493 AC: 2036 AN: 4133

European-Non Finnish (NFE) AF: 0.692 AC: 581920 AN: 841305

Other (OTH) AF: 0.595 AC: 27378 AN: 46043

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

African (AFR) AF: 0.177 AC: 5419 AN: 30686

American (AMR) AF: 0.599 AC: 6208 AN: 10367

Ashkenazi Jewish (ASJ) AF: 0.623 AC: 1633 AN: 2623

East Asian (EAS) AF: 0.361 AC: 1272 AN: 3525

South Asian (SAS) AF: 0.222 AC: 606 AN: 2727

European-Finnish (FIN) AF: 0.693 AC: 4037 AN: 5827

Middle Eastern (MID) AF: 0.502 AC: 108 AN: 215

European-Non Finnish (NFE) AF: 0.681 AC: 36030 AN: 52881

Other (OTH) AF: 0.518 AC: 785 AN: 1515

Alfa AF: 0.592 Hom.: 6823

Bravo AF: 0.497

EpiCase AF: 0.677

EpiControl AF: 0.678

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	1	MEHMO syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	4.2
DANN	Benign	0.80
PhyloP100		0.087
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

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