chr20-48629539-C-G

Position:

• chr20-48629539-C-G

Variant summary

Our verdict is Benign. Variant got -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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• 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

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 Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PREX1	NM_020820.4	c.4676G>C	p.Ser1559Thr	missense_variant	37/40	ENST00000371941.4	NP_065871.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PREX1	ENST00000371941.4	c.4676G>C	p.Ser1559Thr	missense_variant	37/40	1	NM_020820.4	ENSP00000361009.3
PREX1	ENST00000482556.5	n.*94G>C		non_coding_transcript_exon_variant	19/22	2		ENSP00000434632.1
PREX1	ENST00000482556.5	n.*94G>C		3_prime_UTR_variant	19/22	2		ENSP00000434632.1

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

GnomAD3 exomes AF: 0.105 AC: 26453 AN: 251270 Hom.: 1607 AF XY: 0.108 AC XY: 14601 AN XY: 135802

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 SAS exome AF: 0.145

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

Gnomad4 AFR exome AF: 0.0483

Gnomad4 AMR exome AF: 0.136

Gnomad4 ASJ exome AF: 0.148

Gnomad4 EAS exome AF: 0.175

Gnomad4 SAS exome AF: 0.140

Gnomad4 FIN exome AF: 0.0726

Gnomad4 NFE exome AF: 0.0883

Gnomad4 OTH exome AF: 0.0999

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

Gnomad4 AFR AF: 0.0473

Gnomad4 AMR AF: 0.125

Gnomad4 ASJ AF: 0.144

Gnomad4 EAS AF: 0.146

Gnomad4 SAS AF: 0.152

Gnomad4 FIN AF: 0.0662

Gnomad4 NFE AF: 0.0895

Gnomad4 OTH AF: 0.0933

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

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 14, 2018	- -

Computational scores

Source: dbNSFP v4.3

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
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

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

Publications

LitVar

Other links and lift over

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