chr12-6315037-G-T

Position:

• chr12-6315037-G-T

Variant summary

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

The NM_001384598.1(PLEKHG6):​c.327G>T​(p.Arg109Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,640 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: 6.8e-7 (0 hom.)
• Consequence: PLEKHG6 NM_001384598.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.613

Genes affected

PLEKHG6 (HGNC:25562): (pleckstrin homology and RhoGEF domain containing G6) Predicted to enable guanyl-nucleotide exchange factor activity. Predicted to be involved in regulation of small GTPase mediated signal transduction. Located in cell junction and centrosome. [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=0.3048068).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLEKHG6	NM_001384598.1	c.327G>T	p.Arg109Ser	missense_variant	4/16	ENST00000684764.1	NP_001371527.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLEKHG6	ENST00000684764.1	c.327G>T	p.Arg109Ser	missense_variant	4/16		NM_001384598.1	ENSP00000506982.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461640 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727106

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

Apr 12, 2022

The c.327G>T (p.R109S) alteration is located in exon 4 (coding exon 3) of the PLEKHG6 gene. This alteration results from a G to T substitution at nucleotide position 327, causing the arginine (R) at amino acid position 109 to be replaced by a serine (S). 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	0.79
BayesDel_addAF	Uncertain	0.099	D
BayesDel_noAF	Benign	-0.090
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.031	T;.;T;.
Eigen	Benign	0.14
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.84	.;T;T;T
M_CAP	Benign	0.084	D
MetaRNN	Benign	0.30	T;T;T;T
MetaSVM	Benign	-0.55	T
MutationAssessor	Uncertain	2.9	M;.;M;.
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-2.0	N;N;N;N
REVEL	Benign	0.27
Sift	Uncertain	0.0020	D;D;D;D
Sift4G	Uncertain	0.0070	D;D;D;D
Polyphen		0.020	B;P;B;D
Vest4		0.56
MutPred		0.50		Gain of catalytic residue at L110 (P = 9e-04);Gain of catalytic residue at L110 (P = 9e-04);Gain of catalytic residue at L110 (P = 9e-04);.;
MVP		0.52
MPC		0.60
ClinPred		0.95	D
GERP RS		2.1
Varity_R		0.26
gMVP		0.58

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: chr12-6424203;