Genetic Variant PLEKHG3:p.Pro2Ser (chr14-64727635-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001308147.2(PLEKHG3):c.4C>T(p.Pro2Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P2A) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

PLEKHG3
NM_001308147.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.18

Publications

0 publications found

Variant links:

Genes affected

PLEKHG3 (HGNC:20364): (pleckstrin homology and RhoGEF domain containing G3) Predicted to enable guanyl-nucleotide exchange factor activity. Predicted to be involved in regulation of small GTPase mediated signal transduction. Predicted to be located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

PLEKHG3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001308147.2. 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
	PLEKHG3	NM_001308147.2	MANE Select	c.4C>T	p.Pro2Ser	missense	Exon 2 of 17	NP_001295076.1	A1L390-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PLEKHG3	ENST00000247226.13	TSL:1 MANE Select	c.4C>T	p.Pro2Ser	missense	Exon 2 of 17	ENSP00000247226.8	A1L390-1
PLEKHG3	ENST00000634379.2	TSL:1	c.67C>T	p.Pro23Ser	missense	Exon 2 of 17	ENSP00000489373.2	A0A0U1RR71
PLEKHG3	ENST00000471182.7	TSL:5	c.4C>T	p.Pro2Ser	missense	Exon 1 of 17	ENSP00000450945.2	A0A8C8NWT4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000413

AC:

AN:

242042

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000924

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1452732

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

722850

African (AFR)

AF:

0.00

AC:

AN:

33328

American (AMR)

AF:

0.00

AC:

AN:

44582

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26014

East Asian (EAS)

AF:

0.00

AC:

AN:

39604

South Asian (SAS)

AF:

0.00

AC:

AN:

85958

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52184

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5738

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1105324

Other (OTH)

AF:

0.00

AC:

AN:

60000

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000225

Hom.:

ExAC

AF:

0.00000828

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Uncertain

0.038

BayesDel_noAF

Benign

-0.18

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.032

Eigen

Uncertain

0.47

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.77

M_CAP

Benign

0.081

MetaRNN

Uncertain

0.46

MetaSVM

Benign

-0.43

MutationAssessor

Uncertain

2.1

PhyloP100

1.2

PrimateAI

Uncertain

0.62

PROVEAN

Uncertain

-3.4

REVEL

Benign

0.21

Sift

Pathogenic

0.0

Sift4G

Benign

0.19

Polyphen

1.0

Vest4

0.34

MutPred

0.28

Gain of phosphorylation at P2 (P = 0.0145)

MVP

0.83

MPC

0.62

ClinPred

0.94

GERP RS

5.2

PromoterAI

0.017

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.12

gMVP

0.54

Mutation Taster

=73/27

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over