Genetic Variant PREX1:p.Ala1486Ser (chr20-48632347-C-A) – ACMG Classification: Benign (-16 pts)

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_020820.4(PREX1):c.4456G>T(p.Ala1486Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00635 in 1,614,038 control chromosomes in the GnomAD database, including 30 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0049 ( 2 hom., cov: 33)

Exomes 𝑓: 0.0065 ( 28 hom. )

Consequence

PREX1
NM_020820.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.0560

Publications

9 publications found

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0036236942).

BP6

Variant 20-48632347-C-A is Benign according to our data. Variant chr20-48632347-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 711758.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 748 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020820.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PREX1	NM_020820.4	MANE Select	c.4456G>T	p.Ala1486Ser	missense	Exon 35 of 40	NP_065871.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PREX1	ENST00000371941.4	TSL:1 MANE Select	c.4456G>T	p.Ala1486Ser	missense	Exon 35 of 40	ENSP00000361009.3	Q8TCU6-1
PREX1	ENST00000935959.1		c.4384G>T	p.Ala1462Ser	missense	Exon 34 of 39	ENSP00000606018.1
PREX1	ENST00000482556.5	TSL:2	n.2523G>T		non_coding_transcript_exon	Exon 17 of 22	ENSP00000434632.1	H0YDZ4

Frequencies

GnomAD3 genomes

AF:

0.00491

AC:

748

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00150

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00523

Gnomad ASJ

AF:

0.00950

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00518

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00730

Gnomad OTH

AF:

0.00957

GnomAD2 exomes

AF:

0.00527

AC:

1324

AN:

251282

AF XY:

0.00529

show subpopulations

Gnomad AFR exome

AF:

0.00117

Gnomad AMR exome

AF:

0.00494

Gnomad ASJ exome

AF:

0.0108

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00623

Gnomad NFE exome

AF:

0.00752

Gnomad OTH exome

AF:

0.00570

GnomAD4 exome

AF:

0.00650

AC:

9508

AN:

1461698

Hom.:

Cov.:

AF XY:

0.00627

AC XY:

4557

AN XY:

727166

show subpopulations

African (AFR)

AF:

0.00116

AC:

AN:

33480

American (AMR)

AF:

0.00514

AC:

230

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0115

AC:

300

AN:

26134

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39698

South Asian (SAS)

AF:

0.0000580

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00535

AC:

285

AN:

53264

Middle Eastern (MID)

AF:

0.00260

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00749

AC:

8325

AN:

1111986

Other (OTH)

AF:

0.00508

AC:

307

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

580

1160

1740

2320

2900

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

324

648

972

1296

1620

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00491

AC:

748

AN:

152340

Hom.:

Cov.:

AF XY:

0.00458

AC XY:

341

AN XY:

74500

show subpopulations

African (AFR)

AF:

0.00149

AC:

AN:

41586

American (AMR)

AF:

0.00523

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00950

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00518

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00731

AC:

497

AN:

68028

Other (OTH)

AF:

0.00947

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

127

170

212

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00624

Hom.:

Bravo

AF:

0.00512

TwinsUK

AF:

0.00620

AC:

ALSPAC

AF:

0.00856

AC:

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.00756

AC:

ExAC

AF:

0.00521

AC:

632

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00731

EpiControl

AF:

0.00741

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.62

CADD

Benign

4.2

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.034

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.20

LIST_S2

Benign

0.47

M_CAP

Benign

0.011

MetaRNN

Benign

0.0036

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.0

PhyloP100

0.056

PrimateAI

Benign

0.26

PROVEAN

Benign

-0.96

REVEL

Benign

0.024

Sift

Benign

0.082

Sift4G

Benign

0.11

Polyphen

0.0010

Vest4

0.21

MVP

0.25

MPC

0.31

ClinPred

0.012

GERP RS

-0.56

Varity_R

0.26

gMVP

0.23

Mutation Taster

=93/7

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over