20-48630735-A-C

Variant names:

• chr20-48630735-A-C
• rs2089307317
• NM_020820.4:c.4586T>G

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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.62

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.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.838

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PREX1	NM_020820.4	c.4586T>G	p.Ile1529Arg	missense_variant	Exon 36 of 40	ENST00000371941.4	NP_065871.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PREX1	ENST00000371941.4	c.4586T>G	p.Ile1529Arg	missense_variant	Exon 36 of 40	1	NM_020820.4	ENSP00000361009.3
PREX1	ENST00000482556.5	n.*4T>G		non_coding_transcript_exon_variant	Exon 18 of 22	2		ENSP00000434632.1
PREX1	ENST00000482556.5	n.*4T>G		3_prime_UTR_variant	Exon 18 of 22	2		ENSP00000434632.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000180 AC: 259 AN: 1435364 Hom.: 0 Cov.: 30 AF XY: 0.000162 AC XY: 116 AN XY: 715410

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.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 04, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	D
BayesDel_noAF	Uncertain	0.020
CADD	Pathogenic	27
DANN	Uncertain	0.98
DEOGEN2	Benign	0.34	T
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	D
M_CAP	Uncertain	0.088	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Benign	-0.34	T
MutationAssessor	Benign	1.9	L
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-3.2	D
REVEL	Uncertain	0.44
Sift	Benign	0.096	T
Sift4G	Pathogenic	0.0010	D
Polyphen		0.98	D
Vest4		0.86
MutPred		0.59		Gain of disorder (P = 0.0332);
MVP		0.37
MPC		1.4
ClinPred		0.94	D
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

Other links and lift over

dbSNP: rs2089307317; hg19: chr20-47247273;