16-67280924-C-T

Variant names:

• chr16-67280924-C-T
• rs1344556418
• NM_001129729.3:c.638C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001129729.3(PLEKHG4):​c.638C>T​(p.Ala213Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,460,646 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: PLEKHG4 NM_001129729.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.52
• Publications: 0 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.29437923).

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.638C>T	p.Ala213Val	missense	Exon 4 of 22	NP_001123201.1	A0A024R6X4
	PLEKHG4	NM_001129727.3		c.638C>T	p.Ala213Val	missense	Exon 5 of 23	NP_001123199.1	Q58EX7-1
	PLEKHG4	NM_001129728.2		c.638C>T	p.Ala213Val	missense	Exon 4 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.638C>T	p.Ala213Val	missense	Exon 4 of 22	ENSP00000368649.3	Q58EX7-1
	PLEKHG4	ENST00000450733.5	TSL:1	c.395C>T	p.Ala132Val	missense	Exon 2 of 20	ENSP00000398030.1	Q58EX7-2
	PLEKHG4	ENST00000393966.1	TSL:1	n.*223C>T		non_coding_transcript_exon	Exon 2 of 10	ENSP00000462601.1	Q58EX7-3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250392 AF XY: 0.00000738

Gnomad AFR exome AF: 0.0000617

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1460646 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 726708

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52212

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111992

Other (OTH) AF: 0.0000331 AC: 2 AN: 60384

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.074	T
BayesDel_noAF	Benign	-0.34
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.057	T
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.29	T
M_CAP	Benign	0.0076	T
MetaRNN	Benign	0.29	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		1.5
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.091
Sift	Benign	0.043	D
Sift4G	Uncertain	0.050	T
Polyphen		0.91	P
Vest4		0.57
MutPred		0.43		Loss of disorder (P = 0.3056)
MVP		0.42
MPC		0.47
ClinPred		0.83	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.078
gMVP		0.41
Mutation Taster		=86/14	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs1344556418; hg19: chr16-67314827;