Variant 6-150819729-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001029884.3(PLEKHG1):c.1363G>A(p.Gly455Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000298 in 1,612,572 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000032 ( 0 hom. )

Consequence

PLEKHG1
NM_001029884.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.136

Variant links:

Genes affected

PLEKHG1 (HGNC:20884): (pleckstrin homology and RhoGEF domain containing G1) Predicted to enable guanyl-nucleotide exchange factor activity. Predicted to be involved in regulation of small GTPase mediated signal transduction. Located in nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

PLEKHG1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.026788324).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLEKHG1	NM_001029884.3 linkuse as main transcript	c.1363G>A	p.Gly455Ser	missense_variant	13/17	ENST00000696526.1	NP_001025055.1	Q9ULL1Q5JYA6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
PLEKHG1	ENST00000696526.1 linkuse as main transcript	c.1363G>A	p.Gly455Ser	missense_variant	13/17		NM_001029884.3	ENSP00000512689.1	Q9ULL1
PLEKHG1	ENST00000475490.1 linkuse as main transcript	n.904G>A		non_coding_transcript_exon_variant	10/15	1		ENSP00000433107.1	H0YD71
PLEKHG1	ENST00000358517.6 linkuse as main transcript	c.1363G>A	p.Gly455Ser	missense_variant	12/16	5		ENSP00000351318.2	Q9ULL1
PLEKHG1	ENST00000644968.1 linkuse as main transcript	c.1363G>A	p.Gly455Ser	missense_variant	12/16			ENSP00000496254.1	Q9ULL1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152110

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251472

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135910

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000322

AC:

AN:

1460462

Hom.:

Cov.:

AF XY:

0.0000344

AC XY:

AN XY:

726678

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000580

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000333

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152110

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74296

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000900

Hom.:

Bravo

AF:

0.0000340

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 27, 2024

The c.1363G>A (p.G455S) alteration is located in exon 13 (coding exon 11) of the PLEKHG1 gene. This alteration results from a G to A substitution at nucleotide position 1363, causing the glycine (G) at amino acid position 455 to be replaced by a serine (S). 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

Benign

0.071

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.66

CADD

Benign

9.4

DANN

Benign

0.36

DEOGEN2

Benign

0.0049

T;T

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.043

LIST_S2

Benign

0.67

.;T

M_CAP

Benign

0.017

MetaRNN

Benign

0.027

T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

-0.85

N;N

PrimateAI

Benign

0.31

PROVEAN

Benign

1.6

.;N

REVEL

Benign

0.076

Sift

Benign

0.60

.;T

Sift4G

Benign

1.0

.;T

Polyphen

0.0070

B;B

Vest4

0.11

MutPred

0.25

Gain of phosphorylation at G455 (P = 0.0266);Gain of phosphorylation at G455 (P = 0.0266);

MVP

0.38

ClinPred

0.014

GERP RS

0.78

Varity_R

0.039

gMVP

0.44

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over