chr6-150804652-G-A

Position:

• chr6-150804652-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001029884.3(PLEKHG1):​c.823G>A​(p.Val275Met) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 31)
• Consequence: PLEKHG1 NM_001029884.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.05

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.78

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLEKHG1	NM_001029884.3	c.823G>A	p.Val275Met	missense_variant	8/17	ENST00000696526.1	NP_001025055.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLEKHG1	ENST00000696526.1	c.823G>A	p.Val275Met	missense_variant	8/17		NM_001029884.3	ENSP00000512689.1
PLEKHG1	ENST00000475490.1	n.364G>A		non_coding_transcript_exon_variant	5/15	1		ENSP00000433107.1
PLEKHG1	ENST00000358517.6	c.823G>A	p.Val275Met	missense_variant	7/16	5		ENSP00000351318.2
PLEKHG1	ENST00000644968.1	c.823G>A	p.Val275Met	missense_variant	7/16			ENSP00000496254.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

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

Aug 05, 2024

The c.823G>A (p.V275M) alteration is located in exon 8 (coding exon 6) of the PLEKHG1 gene. This alteration results from a G to A substitution at nucleotide position 823, causing the valine (V) at amino acid position 275 to be replaced by a methionine (M). 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	0.47
BayesDel_addAF	Uncertain	0.048	T
BayesDel_noAF	Benign	-0.17
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.20	T;T
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	.;D
M_CAP	Benign	0.020	T
MetaRNN	Pathogenic	0.78	D;D
MetaSVM	Benign	-0.61	T
MutationAssessor	Benign	1.8	L;L
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-2.6	.;D
REVEL	Benign	0.29
Sift	Uncertain	0.028	.;D
Sift4G	Uncertain	0.048	.;D
Polyphen		0.98	D;D
Vest4		0.74
MutPred		0.69		Gain of disorder (P = 0.1344);Gain of disorder (P = 0.1344);
MVP		0.79
ClinPred		0.97	D
GERP RS		6.2
Varity_R		0.38
gMVP		0.41

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs757182373; hg19: chr6-151125788;