Genetic Variant PLEKHG1:p.Glu197Gly (chr6-150795863-A-G) – 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_001029884.3(PLEKHG1):c.590A>G(p.Glu197Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000000691 in 1,446,676 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. E197A) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

PLEKHG1
NM_001029884.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.10

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

periventricular leukomalacia
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

PLEKHG1 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_001029884.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PLEKHG1	NM_001029884.3	MANE Select	c.590A>G	p.Glu197Gly	missense	Exon 6 of 17	NP_001025055.1	Q9ULL1
PLEKHG1	NM_001329798.2		c.767A>G	p.Glu256Gly	missense	Exon 5 of 16	NP_001316727.1
PLEKHG1	NM_001329799.2		c.710A>G	p.Glu237Gly	missense	Exon 5 of 16	NP_001316728.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PLEKHG1	ENST00000696526.1	MANE Select	c.590A>G	p.Glu197Gly	missense	Exon 6 of 17	ENSP00000512689.1	Q9ULL1
PLEKHG1	ENST00000475490.1	TSL:1	n.131A>G		non_coding_transcript_exon	Exon 3 of 15	ENSP00000433107.1	H0YD71
PLEKHG1	ENST00000358517.6	TSL:5	c.590A>G	p.Glu197Gly	missense	Exon 5 of 16	ENSP00000351318.2	Q9ULL1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.91e-7

AC:

AN:

1446676

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

720664

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33160

American (AMR)

AF:

0.00

AC:

AN:

44652

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26004

East Asian (EAS)

AF:

0.00

AC:

AN:

39614

South Asian (SAS)

AF:

0.00

AC:

AN:

85606

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53280

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5738

European-Non Finnish (NFE)

AF:

9.10e-7

AC:

AN:

1098724

Other (OTH)

AF:

0.00

AC:

AN:

59898

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Benign

-0.0026

BayesDel_noAF

Benign

-0.24

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.069

Eigen

Benign

0.024

Eigen_PC

Uncertain

0.24

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.90

M_CAP

Benign

0.019

MetaRNN

Uncertain

0.45

MetaSVM

Benign

-0.93

MutationAssessor

Benign

0.56

PhyloP100

7.1

PrimateAI

Uncertain

0.63

PROVEAN

Pathogenic

-5.1

REVEL

Benign

0.24

Sift

Benign

0.15

Sift4G

Uncertain

0.045

Polyphen

0.26

Vest4

0.28

MutPred

0.62

Loss of stability (P = 0.024)

MVP

0.85

ClinPred

0.94

GERP RS

5.6

Varity_R

0.41

gMVP

0.42

Mutation Taster

=52/48

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.30

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.30

Position offset: -7

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