Variant chr20-48630735-A-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP3

The NM_020820.4(PREX1):c.4586T>G(p.Ile1529Arg) variant causes a missense change involving the alteration of a 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 Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.00018 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

PREX1
NM_020820.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.62

Variant links:

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]

PREX1 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.838

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PREX1	NM_020820.4 link	c.4586T>G	p.Ile1529Arg	missense_variant	36/40	ENST00000371941.4	NP_065871.3	Q8TCU6-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
PREX1	ENST00000371941.4 link	c.4586T>G	p.Ile1529Arg	missense_variant	36/40	1	NM_020820.4	ENSP00000361009.3	Q8TCU6-1
PREX1	ENST00000482556.5 link	n.*4T>G		non_coding_transcript_exon_variant	18/22	2		ENSP00000434632.1	H0YDZ4
PREX1	ENST00000482556.5 link	n.*4T>G		3_prime_UTR_variant	18/22	2		ENSP00000434632.1	H0YDZ4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000180

AC:

259

AN:

1435364

Hom.:

Cov.:

AF XY:

0.000162

AC XY:

116

AN XY:

715410

show subpopulations

Gnomad4 AFR exome

AF:

0.0000608

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000583

Gnomad4 FIN exome

AF:

0.0000188

Gnomad4 NFE exome

AF:

0.000224

Gnomad4 OTH exome

AF:

0.000118

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 04, 2024

The c.4586T>G (p.I1529R) alteration is located in exon 36 (coding exon 36) of the PREX1 gene. This alteration results from a T to G substitution at nucleotide position 4586, causing the isoleucine (I) at amino acid position 1529 to be replaced by an arginine (R). 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

0.92

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Uncertain

0.020

CADD

Pathogenic

DANN

Uncertain

0.98

DEOGEN2

Benign

0.34

Eigen

Uncertain

0.58

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.92

M_CAP

Uncertain

0.088

MetaRNN

Pathogenic

0.84

MetaSVM

Benign

-0.34

MutationAssessor

Benign

1.9

PrimateAI

Uncertain

0.78

PROVEAN

Uncertain

-3.2

REVEL

Uncertain

0.44

Sift

Benign

0.096

Sift4G

Pathogenic

0.0010

Polyphen

0.98

Vest4

0.86

MutPred

0.59

Gain of disorder (P = 0.0332);

MVP

0.37

MPC

1.4

ClinPred

0.94

GERP RS

4.4

Varity_R

0.46

gMVP

0.75

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over