rs8044843

Positions:

• chr16-67284339-A-C
• chr16-67284339-A-G
• chr16-67284339-A-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001129729.3(PLEKHG4):​c.1574A>C​(p.Asp525Ala) 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 benign outcome for this variant. 15/21 in silico tools predict a benign 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. D525G) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PLEKHG4 NM_001129729.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.793

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06553483).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLEKHG4	NM_001129729.3	c.1574A>C	p.Asp525Ala	missense_variant	12/22	ENST00000379344.8	NP_001123201.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLEKHG4	ENST00000379344.8	c.1574A>C	p.Asp525Ala	missense_variant	12/22	1	NM_001129729.3	ENSP00000368649	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	16
DANN	Benign	0.91
DEOGEN2	Benign	0.017	T;T;T;.
Eigen	Benign	-0.88
Eigen_PC	Benign	-0.73
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.26	.;.;T;T
M_CAP	Benign	0.0035	T
MetaRNN	Benign	0.066	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;N;N;.
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.030	N;N;N;N
REVEL	Benign	0.053
Sift	Benign	0.34	T;T;T;T
Sift4G	Benign	0.72	T;T;T;T
Polyphen		0.0	B;B;B;B
Vest4		0.18
MutPred		0.21		Gain of methylation at R530 (P = 0.1063);Gain of methylation at R530 (P = 0.1063);Gain of methylation at R530 (P = 0.1063);.;
MVP		0.21
MPC		0.32
ClinPred		0.21	T
GERP RS		4.5
Varity_R		0.077
gMVP		0.084

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: rs8044843; hg19: chr16-67318242;