rs3868142

Variant names:

• chr16-67286320-G-A
• rs3868142
• NM_001129729.3:c.2489G>A

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001129729.3(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. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.22 (7093 hom., cov: 33)
  • Exomes 𝑓: 0.092 (11258 hom.)
• Consequence: PLEKHG4 NM_001129729.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 2.10
• Publications: 31 publications found

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

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001129729.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLEKHG4	NM_001129729.3	MANE Select	c.2489G>A	p.Arg830His	missense	Exon 15 of 22	NP_001123201.1	A0A024R6X4
	PLEKHG4	NM_001129727.3		c.2489G>A	p.Arg830His	missense	Exon 16 of 23	NP_001123199.1	Q58EX7-1
	PLEKHG4	NM_001129728.2		c.2489G>A	p.Arg830His	missense	Exon 15 of 22	NP_001123200.1	A0A024R6X4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLEKHG4	ENST00000379344.8	TSL:1 MANE Select	c.2489G>A	p.Arg830His	missense	Exon 15 of 22	ENSP00000368649.3	Q58EX7-1
	PLEKHG4	ENST00000450733.5	TSL:1	c.2246G>A	p.Arg749His	missense	Exon 13 of 20	ENSP00000398030.1	Q58EX7-2
	PLEKHG4	ENST00000393966.1	TSL:1	n.*1198+1863G>A		intron	N/A	ENSP00000462601.1	Q58EX7-3

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

GnomAD2 exomes AF: 0.117 AC: 29463 AN: 251458 AF XY: 0.112

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 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

African (AFR) AF: 0.583 AC: 19499 AN: 33458

American (AMR) AF: 0.0689 AC: 3081 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0703 AC: 1836 AN: 26134

East Asian (EAS) AF: 0.00270 AC: 107 AN: 39696

South Asian (SAS) AF: 0.143 AC: 12353 AN: 86240

European-Finnish (FIN) AF: 0.140 AC: 7464 AN: 53408

Middle Eastern (MID) AF: 0.150 AC: 864 AN: 5768

European-Non Finnish (NFE) AF: 0.0739 AC: 82112 AN: 1111482

Other (OTH) AF: 0.111 AC: 6711 AN: 60378

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

African (AFR) AF: 0.560 AC: 23196 AN: 41434

American (AMR) AF: 0.109 AC: 1662 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0605 AC: 210 AN: 3472

East Asian (EAS) AF: 0.00483 AC: 25 AN: 5176

South Asian (SAS) AF: 0.138 AC: 666 AN: 4826

European-Finnish (FIN) AF: 0.148 AC: 1564 AN: 10584

Middle Eastern (MID) AF: 0.177 AC: 52 AN: 294

European-Non Finnish (NFE) AF: 0.0739 AC: 5021 AN: 67972

Other (OTH) AF: 0.161 AC: 340 AN: 2110

Alfa AF: 0.114 Hom.: 10863

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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.11
FATHMM_MKL	Benign	0.45	N
LIST_S2	Uncertain	0.91	D
MetaRNN	Benign	0.0015	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		2.1
PrimateAI	Benign	0.28	T
PROVEAN	Uncertain	-2.7	D
REVEL	Benign	0.10
Sift	Uncertain	0.027	D
Sift4G	Uncertain	0.015	D
Polyphen		0.038	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
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

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