6-150768722-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001029884.3(PLEKHG1):c.496A>G(p.Ile166Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PLEKHG1 NM_001029884.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.30

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLEKHG1	NM_001029884.3	c.496A>G	p.Ile166Val	missense_variant	4/17	ENST00000696526.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLEKHG1	ENST00000696526.1	c.496A>G	p.Ile166Val	missense_variant	4/17		NM_001029884.3	P1
PLEKHG1	ENST00000475490.1	c.37A>G	p.Ile13Val	missense_variant, NMD_transcript_variant	1/15	1
PLEKHG1	ENST00000358517.6	c.496A>G	p.Ile166Val	missense_variant	3/16	5		P1
PLEKHG1	ENST00000644968.1	c.496A>G	p.Ile166Val	missense_variant	3/16			P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 26

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 06, 2023

The c.496A>G (p.I166V) alteration is located in exon 4 (coding exon 2) of the PLEKHG1 gene. This alteration results from a A to G substitution at nucleotide position 496, causing the isoleucine (I) at amino acid position 166 to be replaced by a valine (V). 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	Uncertain	0.56
BayesDel_addAF	Uncertain	0.090	D
BayesDel_noAF	Benign	-0.11
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Benign	0.049	T;T
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Benign	0.045	D
MetaRNN	Uncertain	0.66	D;D
MetaSVM	Uncertain	0.22	D
MutationAssessor	Uncertain	2.5	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.63	T
Polyphen		1.0	D;D
Vest4		0.73
MutPred		0.59		Loss of catalytic residue at I166 (P = 0.0236);Loss of catalytic residue at I166 (P = 0.0236);
MVP		0.85
ClinPred		0.90	D
GERP RS		6.0
Varity_R		0.28
gMVP		0.33

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: rs1212555079; hg19: chr6-151089858;