14-64731439-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001308147.2(PLEKHG3):c.928C>T(p.Arg310Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00118 in 1,613,754 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0018 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (18 hom.)
• Consequence: PLEKHG3 NM_001308147.2 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.85

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009934127).
• BP6: Variant 14-64731439-C-T is Benign according to our data. Variant chr14-64731439-C-T is described in ClinVar as [Benign]. Clinvar id is 789062.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.00111 (1622/1461464) while in subpopulation EAS AF= 0.0195 (775/39692). AF 95% confidence interval is 0.0184. There are 18 homozygotes in gnomad4_exome. There are 749 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLEKHG3	NM_001308147.2	c.928C>T	p.Arg310Cys	missense_variant	8/17	ENST00000247226.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLEKHG3	ENST00000247226.13	c.928C>T	p.Arg310Cys	missense_variant	8/17	1	NM_001308147.2	A2

Frequencies

GnomAD3 genomes AF: 0.00183 AC: 279 AN: 152172 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0106

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.0160

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.000480

GnomAD3 exomes AF: 0.00379 AC: 952 AN: 251450 Hom.: 7 AF XY: 0.00318 AC XY: 432 AN XY: 135906

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.0153

Gnomad ASJ exome AF: 0.00288

Gnomad EAS exome AF: 0.0189

Gnomad SAS exome AF: 0.000457

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000106

Gnomad OTH exome AF: 0.00228

GnomAD4 exome AF: 0.00111 AC: 1622 AN: 1461464 Hom.: 18 Cov.: 33 AF XY: 0.00103 AC XY: 749 AN XY: 727086

Gnomad4 AFR exome AF: 0.000239

Gnomad4 AMR exome AF: 0.0135

Gnomad4 ASJ exome AF: 0.00222

Gnomad4 EAS exome AF: 0.0195

Gnomad4 SAS exome AF: 0.000533

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000711

Gnomad4 OTH exome AF: 0.000795

GnomAD4 genome AF: 0.00183 AC: 278 AN: 152290 Hom.: 4 Cov.: 32 AF XY: 0.00250 AC XY: 186 AN XY: 74454

Gnomad4 AFR AF: 0.000361

Gnomad4 AMR AF: 0.0105

Gnomad4 ASJ AF: 0.00259

Gnomad4 EAS AF: 0.0163

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00131 Hom.: 2

Bravo AF: 0.00295

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.00332 AC: 403

Asia WGS AF: 0.00606 AC: 22 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000237

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Sep 10, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Benign	-0.065	T
BayesDel_noAF	Pathogenic	0.15
Cadd	Pathogenic	33
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.089	T;.;T
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.99	D;D;D
MetaRNN	Benign	0.0099	T;T;T
MetaSVM	Uncertain	0.52	D
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.57	T
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		0.99, 1.0	.;D;D
Vest4		0.88, 0.84
MVP		0.92
MPC		0.61
ClinPred		0.058	T
GERP RS		4.6
Varity_R		0.48
gMVP		0.50

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: rs145013864; hg19: chr14-65198157;