16-67280890-G-A

Variant names:

• chr16-67280890-G-A
• rs902297806
• NM_001129729.3:c.604G>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001129729.3(PLEKHG4):​c.604G>A​(p.Asp202Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,460,560 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: PLEKHG4 NM_001129729.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.45

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLEKHG4	NM_001129729.3	c.604G>A	p.Asp202Asn	missense_variant	Exon 4 of 22	ENST00000379344.8	NP_001123201.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLEKHG4	ENST00000379344.8	c.604G>A	p.Asp202Asn	missense_variant	Exon 4 of 22	1	NM_001129729.3	ENSP00000368649.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1460560 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 726658

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 24, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.604G>A (p.D202N) alteration is located in exon 3 (coding exon 3) of the PLEKHG4 gene. This alteration results from a G to A substitution at nucleotide position 604, causing the aspartic acid (D) at amino acid position 202 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Uncertain	0.041	T
BayesDel_noAF	Benign	-0.18
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.53	D;T;D;D;.
Eigen	Pathogenic	0.74
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.32	.;T;.;D;D
M_CAP	Uncertain	0.090	D
MetaRNN	Uncertain	0.72	D;D;D;D;D
MetaSVM	Uncertain	0.30	D
MutationAssessor	Pathogenic	3.5	H;.;H;H;.
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-4.0	D;N;D;D;D
REVEL	Uncertain	0.47
Sift	Pathogenic	0.0	D;T;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D
Polyphen		1.0	D;.;D;D;D
Vest4		0.77
MutPred		0.65		Gain of catalytic residue at D202 (P = 0.0595);.;Gain of catalytic residue at D202 (P = 0.0595);Gain of catalytic residue at D202 (P = 0.0595);.;
MVP		0.84
MPC		0.91
ClinPred		0.99	D
GERP RS		5.7
Varity_R		0.43
gMVP		0.85

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: rs902297806; hg19: chr16-67314793;