chr20-48629539-C-G

Variant names:

• chr20-48629539-C-G
• rs3936192
• NM_020820.4:c.4676G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_020820.4(PREX1):​c.4676G>C​(p.Ser1559Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0943 in 1,614,048 control chromosomes in the GnomAD database, including 8,054 homozygotes. 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 Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S1559N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.085 (624 hom., cov: 32)
  • Exomes 𝑓: 0.095 (7430 hom.)
• Consequence: PREX1 NM_020820.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.90
• Publications: 22 publications found

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

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0016014576).
• BP6: Variant 20-48629539-C-G is Benign according to our data. Variant chr20-48629539-C-G is described in ClinVar as Benign. ClinVar VariationId is 1296867.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.143 is higher than 0.05.

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.4676G>C	p.Ser1559Thr	missense	Exon 37 of 40	NP_065871.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PREX1	ENST00000371941.4	TSL:1 MANE Select	c.4676G>C	p.Ser1559Thr	missense	Exon 37 of 40	ENSP00000361009.3	Q8TCU6-1
	PREX1	ENST00000935959.1		c.4604G>C	p.Ser1535Thr	missense	Exon 36 of 39	ENSP00000606018.1
	PREX1	ENST00000482556.5	TSL:2	n.*94G>C		non_coding_transcript_exon	Exon 19 of 22	ENSP00000434632.1	H0YDZ4

Frequencies

GnomAD3 genomes AF: 0.0849 AC: 12926 AN: 152174 Hom.: 625 Cov.: 32

Gnomad AFR AF: 0.0471

Gnomad AMI AF: 0.0505

Gnomad AMR AF: 0.125

Gnomad ASJ AF: 0.144

Gnomad EAS AF: 0.146

Gnomad SAS AF: 0.153

Gnomad FIN AF: 0.0662

Gnomad MID AF: 0.104

Gnomad NFE AF: 0.0895

Gnomad OTH AF: 0.0947

GnomAD2 exomes AF: 0.105 AC: 26453 AN: 251270 AF XY: 0.108

Gnomad AFR exome AF: 0.0475

Gnomad AMR exome AF: 0.134

Gnomad ASJ exome AF: 0.147

Gnomad EAS exome AF: 0.141

Gnomad FIN exome AF: 0.0682

Gnomad NFE exome AF: 0.0915

Gnomad OTH exome AF: 0.111

GnomAD4 exome AF: 0.0953 AC: 139324 AN: 1461756 Hom.: 7430 Cov.: 32 AF XY: 0.0970 AC XY: 70571 AN XY: 727182

African (AFR) AF: 0.0483 AC: 1616 AN: 33478

American (AMR) AF: 0.136 AC: 6076 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.148 AC: 3865 AN: 26128

East Asian (EAS) AF: 0.175 AC: 6949 AN: 39698

South Asian (SAS) AF: 0.140 AC: 12093 AN: 86250

European-Finnish (FIN) AF: 0.0726 AC: 3879 AN: 53412

Middle Eastern (MID) AF: 0.106 AC: 609 AN: 5766

European-Non Finnish (NFE) AF: 0.0883 AC: 98202 AN: 1111928

Other (OTH) AF: 0.0999 AC: 6035 AN: 60386

GnomAD4 genome AF: 0.0849 AC: 12937 AN: 152292 Hom.: 624 Cov.: 32 AF XY: 0.0860 AC XY: 6407 AN XY: 74472

African (AFR) AF: 0.0473 AC: 1967 AN: 41576

American (AMR) AF: 0.125 AC: 1917 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.144 AC: 501 AN: 3472

East Asian (EAS) AF: 0.146 AC: 755 AN: 5174

South Asian (SAS) AF: 0.152 AC: 735 AN: 4826

European-Finnish (FIN) AF: 0.0662 AC: 703 AN: 10620

Middle Eastern (MID) AF: 0.105 AC: 31 AN: 294

European-Non Finnish (NFE) AF: 0.0895 AC: 6085 AN: 68006

Other (OTH) AF: 0.0933 AC: 197 AN: 2112

Alfa AF: 0.0950 Hom.: 574

Bravo AF: 0.0869

TwinsUK AF: 0.0833 AC: 309

ALSPAC AF: 0.0924 AC: 356

ESP6500AA AF: 0.0504 AC: 222

ESP6500EA AF: 0.0943 AC: 811

ExAC AF: 0.103 AC: 12524

Asia WGS AF: 0.125 AC: 434 AN: 3478

EpiCase AF: 0.0940

EpiControl AF: 0.0959

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	13
DANN	Benign	0.73
DEOGEN2	Benign	0.028	T
Eigen	Benign	-0.88
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.60	T
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.34	N
PhyloP100		1.9
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.76	N
REVEL	Benign	0.030
Sift	Benign	0.20	T
Sift4G	Benign	0.36	T
Polyphen		0.35	B
Vest4		0.066
MPC		0.34
ClinPred		0.0064	T
GERP RS		1.8
Varity_R		0.047
gMVP		0.29
Mutation Taster		=96/4	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs3936192; hg19: chr20-47246077; COSMIC: COSV64248606;