chrX-51743942-C-CG

Variant names:

• chrX-51743942-C-CG
• rs398124340
• NM_018094.5:c.322dupG

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_018094.5(GSPT2):​c.322dupG​(p.Ala108GlyfsTer15) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000275 in 1,092,072 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000027 (0 hom. 0 hem.)
• Consequence: GSPT2 NM_018094.5 frameshift
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.10
• Publications: 1 publications found

Genes affected

GSPT2 (HGNC:4622): (G1 to S phase transition 2) This gene encodes a GTPase that belongs to the GTP-binding elongation factor family. The encoded protein is a polypeptide release factor that complexes with eukaryotic peptide chain release factor 1 to mediate translation termination. This protein may also be involved in mRNA stability.[provided by RefSeq, Mar 2010]

GSPT2 Gene-Disease associations (from GenCC):

• intellectual disability

  Inheritance: XL Classification: STRONG Submitted by: G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018094.5. 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
	GSPT2	NM_018094.5	MANE Select	c.322dupG	p.Ala108GlyfsTer15	frameshift	Exon 1 of 1	NP_060564.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GSPT2	ENST00000340438.6	TSL:6 MANE Select	c.322dupG	p.Ala108GlyfsTer15	frameshift	Exon 1 of 1	ENSP00000341247.4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD2 exomes AF: 0.00000605 AC: 1 AN: 165211 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000240

GnomAD4 exome AF: 0.00000275 AC: 3 AN: 1092072 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 358210

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 26298

American (AMR) AF: 0.00 AC: 0 AN: 34616

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19250

East Asian (EAS) AF: 0.00 AC: 0 AN: 30002

South Asian (SAS) AF: 0.00 AC: 0 AN: 53088

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39842

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4127

European-Non Finnish (NFE) AF: 0.00000238 AC: 2 AN: 838969

Other (OTH) AF: 0.0000218 AC: 1 AN: 45880

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0556734), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 23

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.1

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: rs398124340; hg19: chrX-51487038; COSMIC: COSV61215535;