20-48629536-A-C

Position:

• chr20-48629536-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_020820.4(PREX1):​c.4679T>G​(p.Val1560Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PREX1 NM_020820.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.93

Genes affected

PREX1 (HGNC:32594): (phosphatidylinositol-3,4,5-trisphosphate dependent Rac exchange factor 1) The protein encoded by this gene acts as a guanine nucleotide exchange factor for the RHO family of small GTP-binding proteins (RACs). It has been shown to bind to and activate RAC1 by exchanging bound GDP for free GTP. The encoded protein, which is found mainly in the cytoplasm, is activated by phosphatidylinositol-3,4,5-trisphosphate and the beta-gamma subunits of heterotrimeric G proteins. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, PREX1
• BP4: Computational evidence support a benign effect (MetaRNN=0.11637458).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PREX1	NM_020820.4	c.4679T>G	p.Val1560Gly	missense_variant	37/40	ENST00000371941.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PREX1	ENST00000371941.4	c.4679T>G	p.Val1560Gly	missense_variant	37/40	1	NM_020820.4	P1
PREX1	ENST00000482556.5	c.*97T>G		3_prime_UTR_variant, NMD_transcript_variant	19/22	2

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 28, 2023

The c.4679T>G (p.V1560G) alteration is located in exon 37 (coding exon 37) of the PREX1 gene. This alteration results from a T to G substitution at nucleotide position 4679, causing the valine (V) at amino acid position 1560 to be replaced by a glycine (G). 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	Benign	0.071
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	17
DANN	Benign	0.81
DEOGEN2	Benign	0.041	T
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.51
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.13	T
M_CAP	Benign	0.062	D
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.23	N
REVEL	Benign	0.18
Sift	Benign	0.27	T
Sift4G	Benign	0.40	T
Polyphen		0.010	B
Vest4		0.23
MutPred		0.37		Gain of disorder (P = 0.012);
MVP		0.24
MPC		0.46
ClinPred		0.12	T
GERP RS		1.3
Varity_R		0.084
gMVP		0.20

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr20-47246074;