6-150830601-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001029884.3(PLEKHG1):c.1490C>A(p.Ser497Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. 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: 2.31

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20432562).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLEKHG1	NM_001029884.3	c.1490C>A	p.Ser497Tyr	missense_variant	16/17	ENST00000696526.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLEKHG1	ENST00000696526.1	c.1490C>A	p.Ser497Tyr	missense_variant	16/17		NM_001029884.3	P1
PLEKHG1	ENST00000475490.1	c.1031C>A	p.Ser344Tyr	missense_variant, NMD_transcript_variant	13/15	1
PLEKHG1	ENST00000358517.6	c.1490C>A	p.Ser497Tyr	missense_variant	15/16	5		P1
PLEKHG1	ENST00000644968.1	c.1490C>A	p.Ser497Tyr	missense_variant	15/16			P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

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

Oct 27, 2023

The c.1490C>A (p.S497Y) alteration is located in exon 16 (coding exon 14) of the PLEKHG1 gene. This alteration results from a C to A substitution at nucleotide position 1490, causing the serine (S) at amino acid position 497 to be replaced by a tyrosine (Y). 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	0.096
BayesDel_addAF	Benign	-0.062	T
BayesDel_noAF	Benign	-0.33
Cadd	Uncertain	23
Dann	Uncertain	0.99
DEOGEN2	Benign	0.012	T;T
Eigen	Benign	0.13
Eigen_PC	Benign	0.062
FATHMM_MKL	Benign	0.68	D
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.20	T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Uncertain	2.4	M;M
MutationTaster	Benign	0.97	N;N
PrimateAI	Benign	0.34	T
Polyphen		0.94	P;P
Vest4		0.37
MutPred		0.15		Gain of glycosylation at S502 (P = 0.1353);Gain of glycosylation at S502 (P = 0.1353);
MVP		0.82
ClinPred		0.90	D
GERP RS		4.2
Varity_R		0.13
gMVP		0.41

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: rs1776860139; hg19: chr6-151151737;