6-150830736-T-G

Variant summary

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

The NM_001029884.3(PLEKHG1):c.1625T>G(p.Leu542Trp) variant causes a missense change involving the alteration of a conserved nucleotide. 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: 7.43

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.1625T>G	p.Leu542Trp	missense_variant	16/17	ENST00000696526.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLEKHG1	ENST00000696526.1	c.1625T>G	p.Leu542Trp	missense_variant	16/17		NM_001029884.3	P1
PLEKHG1	ENST00000475490.1	c.1157+9T>G		intron_variant, NMD_transcript_variant		1
PLEKHG1	ENST00000358517.6	c.1625T>G	p.Leu542Trp	missense_variant	15/16	5		P1
PLEKHG1	ENST00000644968.1	c.1625T>G	p.Leu542Trp	missense_variant	15/16			P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

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

Jun 07, 2023

The c.1625T>G (p.L542W) alteration is located in exon 16 (coding exon 14) of the PLEKHG1 gene. This alteration results from a T to G substitution at nucleotide position 1625, causing the leucine (L) at amino acid position 542 to be replaced by a tryptophan (W). 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	Pathogenic	0.58
BayesDel_addAF	Uncertain	0.095	D
BayesDel_noAF	Benign	-0.10
Cadd	Pathogenic	27
Dann	Benign	0.96
DEOGEN2	Benign	0.11	T;T
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Benign	0.067	D
MetaRNN	Uncertain	0.60	D;D
MetaSVM	Uncertain	-0.22	T
MutationAssessor	Uncertain	2.7	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.60	T
Polyphen		1.0	D;D
Vest4		0.69
MutPred		0.32		Loss of stability (P = 0.0199);Loss of stability (P = 0.0199);
MVP		0.96
ClinPred		0.99	D
GERP RS		5.4
Varity_R		0.50
gMVP		0.73

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-151151872;