16-67284339-A-C

Variant names:

• chr16-67284339-A-C
• rs8044843
• NM_001129729.3:c.1574A>C

Variant summary

Our verdict is Likely benign. The variant received -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. 16/22 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 Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PLEKHG4 NM_001129729.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.793
• Publications: 36 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: Likely_benign. The variant received -2 ACMG points.

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

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLEKHG4	NM_001129729.3	MANE Select	c.1574A>C	p.Asp525Ala	missense	Exon 12 of 22	NP_001123201.1
	PLEKHG4	NM_001129727.3		c.1574A>C	p.Asp525Ala	missense	Exon 13 of 23	NP_001123199.1
	PLEKHG4	NM_001129728.2		c.1574A>C	p.Asp525Ala	missense	Exon 12 of 22	NP_001123200.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLEKHG4	ENST00000379344.8	TSL:1 MANE Select	c.1574A>C	p.Asp525Ala	missense	Exon 12 of 22	ENSP00000368649.3
	PLEKHG4	ENST00000450733.5	TSL:1	c.1331A>C	p.Asp444Ala	missense	Exon 10 of 20	ENSP00000398030.1
	PLEKHG4	ENST00000393966.1	TSL:1	n.*1080A>C		non_coding_transcript_exon	Exon 9 of 10	ENSP00000462601.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 4865

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.88
Eigen_PC	Benign	-0.73
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.26	T
M_CAP	Benign	0.0035	T
MetaRNN	Benign	0.066	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.79
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.030	N
REVEL	Benign	0.053
Sift	Benign	0.34	T
Sift4G	Benign	0.72	T
Polyphen		0.0	B
Vest4		0.18
MutPred		0.21		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

Other links and lift over

dbSNP: rs8044843; hg19: chr16-67318242;