17-7313051-A-T

Variant names:

• chr17-7313051-A-T
• NM_004489.5:c.878T>A

Variant summary

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

The NM_004489.5(GPS2):​c.878T>A​(p.Val293Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GPS2 NM_004489.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.47

Genes affected

GPS2 (HGNC:4550): (G protein pathway suppressor 2) This gene encodes a protein involved in G protein-mitogen-activated protein kinase (MAPK) signaling cascades. When overexpressed in mammalian cells, this gene could potently suppress a RAS- and MAPK-mediated signal and interfere with JNK activity, suggesting that the function of this gene may be signal repression. The encoded protein is an integral subunit of the NCOR1-HDAC3 (nuclear receptor corepressor 1-histone deacetylase 3) complex, and it was shown that the complex inhibits JNK activation through this subunit and thus could potentially provide an alternative mechanism for hormone-mediated antagonism of AP1 (activator protein 1) function. [provided by RefSeq, Jul 2008]

ENSG00000261915 (HGNC:):

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 rank	MANE	Protein	UniProt
GPS2	NM_004489.5	c.878T>A	p.Val293Glu	missense_variant	Exon 10 of 11	ENST00000380728.7	NP_004480.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GPS2	ENST00000380728.7	c.878T>A	p.Val293Glu	missense_variant	Exon 10 of 11	1	NM_004489.5	ENSP00000370104.2
ENSG00000261915	ENST00000575474.1	n.*1153T>A		non_coding_transcript_exon_variant	Exon 18 of 19	5		ENSP00000468772.1
ENSG00000261915	ENST00000575474.1	n.*1153T>A		3_prime_UTR_variant	Exon 18 of 19	5		ENSP00000468772.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 19, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.878T>A (p.V293E) alteration is located in exon 10 (coding exon 9) of the GPS2 gene. This alteration results from a T to A substitution at nucleotide position 878, causing the valine (V) at amino acid position 293 to be replaced by a glutamic acid (E). 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	0.81
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Pathogenic	27
DANN	Uncertain	0.98
DEOGEN2	Benign	0.16	T;T;T
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.74	T;.;T
M_CAP	Benign	0.064	D
MetaRNN	Uncertain	0.48	T;T;T
MetaSVM	Benign	-0.64	T
MutationAssessor	Benign	1.6	.;L;L
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-0.74	.;N;N
REVEL	Benign	0.24
Sift	Pathogenic	0.0	.;D;D
Sift4G	Pathogenic	0.0	D;T;T
Polyphen		1.0	.;D;D
Vest4		0.73
MutPred		0.21		.;Gain of solvent accessibility (P = 0.0058);Gain of solvent accessibility (P = 0.0058);
MVP		0.85
ClinPred		0.93	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.67
gMVP		0.65

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-7216370;