14-64730827-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001308147.2(PLEKHG3):c.595C>T(p.Arg199Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000151 in 1,461,090 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: PLEKHG3 NM_001308147.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.61

Genes affected

PLEKHG3 (HGNC:20364): (pleckstrin homology and RhoGEF domain containing G3) Predicted to enable guanyl-nucleotide exchange factor activity. Predicted to be involved in regulation of small GTPase mediated signal transduction. Predicted to be located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3690614).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLEKHG3	NM_001308147.2	c.595C>T	p.Arg199Trp	missense_variant	6/17	ENST00000247226.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLEKHG3	ENST00000247226.13	c.595C>T	p.Arg199Trp	missense_variant	6/17	1	NM_001308147.2	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000120 AC: 3 AN: 250442 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 135444

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000151 AC: 22 AN: 1461090 Hom.: 0 Cov.: 34 AF XY: 0.0000206 AC XY: 15 AN XY: 726868

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000117

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000712 Hom.: 0

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.0000545

EpiControl AF: 0.00

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

Nov 15, 2021

The c.427C>T (p.R143W) alteration is located in exon 4 (coding exon 3) of the PLEKHG3 gene. This alteration results from a C to T substitution at nucleotide position 427, causing the arginine (R) at amino acid position 143 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	Benign	0.20
BayesDel_addAF	Benign	-0.088	T
BayesDel_noAF	Benign	-0.18
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Benign	0.35	T;.;T
Eigen	Benign	0.095
Eigen_PC	Benign	0.0092
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.97	D;D;D
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.37	T;T;T
MetaSVM	Uncertain	0.039	D
MutationTaster	Benign	0.74	D;N
PrimateAI	Benign	0.30	T
Sift4G	Uncertain	0.0030	D;D;D
Polyphen		1.0, 1.0	.;D;D
Vest4		0.55, 0.53
MutPred		0.36		.;.;Loss of disorder (P = 0.0259);
MVP		0.69
MPC		0.56
ClinPred		0.98	D
GERP RS		2.7
Varity_R		0.81
gMVP		0.30

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: rs767234154; hg19: chr14-65197545; COSMIC: COSV105059007; COSMIC: COSV105059007;