8-68022056-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PM4

The NM_024870.4(PREX2):c.357T>A(p.Tyr119Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as not provided (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PREX2 NM_024870.4 stop_gained
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 0.0640

Genes affected

PREX2 (HGNC:22950): (phosphatidylinositol-3,4,5-trisphosphate dependent Rac exchange factor 2) The protein encoded by this gene belongs to the phosphatidylinositol 3,4,5-trisphosphate (PIP3)-dependent Rac exchanger (PREX) family, which are Dbl-type guanine-nucleotide exchange factors for Rac family small G proteins. Structural domains of this protein include the catalytic diffuse B-cell lymphoma homology and pleckstrin homology (DHPH) domain, two disheveled, EGL-10, and pleckstrin homology (DEP) domains, two PDZ domains, and a C-terminal inositol polyphosphate-4 phosphatase (IP4P) domain that is found in one of the isoforms. This protein facilitates the exchange of GDP for GTP on Rac1, allowing the GTP-bound Rac1 to activate downstream effectors. Studies also show that the pleckstrin homology domain of this protein interacts with the phosphatase and tensin homolog (PTEN) gene product to inhibit PTEN phosphatase activity, thus activating the phosphoinositide-3 kinase (PI3K) signaling pathway. Conversely, the PTEN gene product has also been shown to inhibit the GEF activity of this protein. This gene plays a role in insulin-signaling pathways, and either mutations or overexpression of this gene have been observed in some cancers. [provided by RefSeq, Apr 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Stoplost variant in NM_024870.4 Downstream stopcodon found after 1722 codons.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PREX2	NM_024870.4	c.357T>A	p.Tyr119Ter	stop_gained	4/40	ENST00000288368.5
PREX2	NM_025170.6	c.357T>A	p.Tyr119Ter	stop_gained	4/24
PREX2	XM_047422267.1	c.222T>A	p.Tyr74Ter	stop_gained	4/40
PREX2	XM_047422268.1	c.357T>A	p.Tyr119Ter	stop_gained	4/28

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PREX2	ENST00000288368.5	c.357T>A	p.Tyr119Ter	stop_gained	4/40	1	NM_024870.4	P1
PREX2	ENST00000529398.5	n.384T>A		non_coding_transcript_exon_variant	4/24	1
PREX2	ENST00000517617.1	n.68T>A		non_coding_transcript_exon_variant	2/24	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 21

GnomAD4 genome Cov.: 32

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

not provided Other:1

not provided, no classification provided

phenotyping only

GenomeConnect, ClinGen

-

Variant interpretted as Uncertain significance and reported on 02-24-2017 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.50
Cadd	Pathogenic	34
Dann	Uncertain	0.99
Eigen	Uncertain	0.40
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.78	D
MutationTaster	Benign	1.0	A
Vest4		0.80
GERP RS		-0.18

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs1807584458; hg19: chr8-68934291;