chr16-67286320-G-C

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001129729.3(PLEKHG4):​c.2489G>C​(p.Arg830Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R830H) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PLEKHG4 NM_001129729.3 missense
• Clinical Significance: Not reported in ClinVar
• 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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.765

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLEKHG4	NM_001129729.3	c.2489G>C	p.Arg830Pro	missense_variant	Exon 15 of 22	ENST00000379344.8	NP_001123201.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLEKHG4	ENST00000379344.8	c.2489G>C	p.Arg830Pro	missense_variant	Exon 15 of 22	1	NM_001129729.3	ENSP00000368649.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.64
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	T;T;T;.
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Benign	0.47	N
LIST_S2	Uncertain	0.97	.;.;D;D
M_CAP	Uncertain	0.10	D
MetaRNN	Pathogenic	0.76	D;D;D;D
MetaSVM	Uncertain	-0.19	T
MutationAssessor	Pathogenic	3.3	M;M;M;.
PrimateAI	Benign	0.30	T
PROVEAN	Uncertain	-3.9	D;D;D;D
REVEL	Uncertain	0.38
Sift	Uncertain	0.024	D;D;D;D
Sift4G	Uncertain	0.013	D;D;D;D
Polyphen		0.98	D;D;D;D
Vest4		0.66
MutPred		0.61		Gain of catalytic residue at P829 (P = 0.0133);Gain of catalytic residue at P829 (P = 0.0133);Gain of catalytic residue at P829 (P = 0.0133);.;
MVP		0.80
MPC		1.1
ClinPred		0.96	D
GERP RS		2.4
Varity_R		0.88
gMVP		0.76

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: rs3868142; hg19: chr16-67320223;