rs3868142

Positions:

• chr16-67286320-G-A
• chr16-67286320-G-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The ENST00000379344.8(PLEKHG4):​c.2489G>A​(p.Arg830His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.103 in 1,613,356 control chromosomes in the GnomAD database, including 18,351 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.22 (7093 hom., cov: 33)
  • Exomes 𝑓: 0.092 (11258 hom.)
• Consequence: PLEKHG4 ENST00000379344.8 missense
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 2.10

Genes affected

PLEKHG4 (HGNC:24501): (pleckstrin homology and RhoGEF domain containing G4) The protein encoded by this gene can function as a guanine nucleotide exchange factor (GEF) and may play a role in intracellular signaling and cytoskeleton dynamics at the Golgi apparatus. Polymorphisms in the region of this gene have been found to be associated with spinocerebellar ataxia in some study populations. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2015]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0014715791).
• BP6: Variant 16-67286320-G-A is Benign according to our data. Variant chr16-67286320-G-A is described in ClinVar as [Benign]. Clinvar id is 129966.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.554 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLEKHG4	NM_001129729.3	c.2489G>A	p.Arg830His	missense_variant	15/22	ENST00000379344.8	NP_001123201.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLEKHG4	ENST00000379344.8	c.2489G>A	p.Arg830His	missense_variant	15/22	1	NM_001129729.3	ENSP00000368649	P2

Frequencies

GnomAD3 genomes AF: 0.215 AC: 32727 AN: 151952 Hom.: 7059 Cov.: 33

Gnomad AFR AF: 0.559

Gnomad AMI AF: 0.0779

Gnomad AMR AF: 0.109

Gnomad ASJ AF: 0.0605

Gnomad EAS AF: 0.00482

Gnomad SAS AF: 0.139

Gnomad FIN AF: 0.148

Gnomad MID AF: 0.184

Gnomad NFE AF: 0.0739

Gnomad OTH AF: 0.163

GnomAD3 exomes AF: 0.117 AC: 29463 AN: 251458 Hom.: 3759 AF XY: 0.112 AC XY: 15271 AN XY: 135912

Gnomad AFR exome AF: 0.570

Gnomad AMR exome AF: 0.0656

Gnomad ASJ exome AF: 0.0681

Gnomad EAS exome AF: 0.00402

Gnomad SAS exome AF: 0.152

Gnomad FIN exome AF: 0.140

Gnomad NFE exome AF: 0.0783

Gnomad OTH exome AF: 0.0950

GnomAD4 exome AF: 0.0917 AC: 134027 AN: 1461286 Hom.: 11258 Cov.: 32 AF XY: 0.0916 AC XY: 66603 AN XY: 726994

Gnomad4 AFR exome AF: 0.583

Gnomad4 AMR exome AF: 0.0689

Gnomad4 ASJ exome AF: 0.0703

Gnomad4 EAS exome AF: 0.00270

Gnomad4 SAS exome AF: 0.143

Gnomad4 FIN exome AF: 0.140

Gnomad4 NFE exome AF: 0.0739

Gnomad4 OTH exome AF: 0.111

GnomAD4 genome AF: 0.216 AC: 32807 AN: 152070 Hom.: 7093 Cov.: 33 AF XY: 0.214 AC XY: 15919 AN XY: 74326

Gnomad4 AFR AF: 0.560

Gnomad4 AMR AF: 0.109

Gnomad4 ASJ AF: 0.0605

Gnomad4 EAS AF: 0.00483

Gnomad4 SAS AF: 0.138

Gnomad4 FIN AF: 0.148

Gnomad4 NFE AF: 0.0739

Gnomad4 OTH AF: 0.161

Alfa AF: 0.0961 Hom.: 3640

Bravo AF: 0.224

TwinsUK AF: 0.0777 AC: 288

ALSPAC AF: 0.0773 AC: 298

ESP6500AA AF: 0.550 AC: 2418

ESP6500EA AF: 0.0751 AC: 646

ExAC AF: 0.129 AC: 15643

Asia WGS AF: 0.121 AC: 422 AN: 3478

EpiCase AF: 0.0740

EpiControl AF: 0.0764

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, no assertion criteria provided

clinical testing

Genetic Services Laboratory, University of Chicago

-

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	T;T;T;.
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.11
FATHMM_MKL	Benign	0.45	N
LIST_S2	Uncertain	0.91	.;.;D;D
MetaRNN	Benign	0.0015	T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Uncertain	2.6	M;M;M;.
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Benign	0.28	T
PROVEAN	Uncertain	-2.7	D;D;D;D
REVEL	Benign	0.10
Sift	Uncertain	0.027	D;D;D;D
Sift4G	Uncertain	0.015	D;D;D;D
Polyphen		0.038	B;B;B;B
Vest4		0.080
MPC		0.36
ClinPred		0.024	T
GERP RS		2.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.095
gMVP		0.18

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: rs3868142; hg19: chr16-67320223; COSMIC: COSV58574213; COSMIC: COSV58574213;