X-51743785-C-A

Position:

• chrX-51743785-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_018094.5(GSPT2):​c.159C>A​(p.Asn53Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000177 in 112,721 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.000018 (0 hom., 0 hem., cov: 24)
• Consequence: GSPT2 NM_018094.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.02

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GSPT2	NM_018094.5	c.159C>A	p.Asn53Lys	missense_variant	1/1	ENST00000340438.6	NP_060564.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GSPT2	ENST00000340438.6	c.159C>A	p.Asn53Lys	missense_variant	1/1	6	NM_018094.5	ENSP00000341247.4

Frequencies

GnomAD3 genomes AF: 0.0000177 AC: 2 AN: 112721 Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0 AN XY: 34865

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000186

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome AF: 0.0000177 AC: 2 AN: 112721 Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0 AN XY: 34865

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000186

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000227

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 17, 2024

The c.159C>A (p.N53K) alteration is located in exon 1 (coding exon 1) of the GSPT2 gene. This alteration results from a C to A substitution at nucleotide position 159, causing the asparagine (N) at amino acid position 53 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	T
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.13	D
MetaRNN	Uncertain	0.56	D
MetaSVM	Benign	-0.76	T
MutationAssessor	Uncertain	2.2	M
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-2.7	D
REVEL	Uncertain	0.31
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.043	D
Polyphen		1.0	D
Vest4		0.27
MutPred		0.77		Gain of methylation at N53 (P = 0.0087);
MVP		0.58
MPC		1.2
ClinPred		0.97	D
GERP RS		0.87
Varity_R		0.74
gMVP		0.69

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: rs781994793; hg19: chrX-51486881;