Genetic Variant PLEKHG4:p.Ala213Gly (chr16-67280924-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001129729.3(PLEKHG4):c.638C>G(p.Ala213Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000685 in 1,460,648 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 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. A213V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000068 ( 0 hom. )

Consequence

PLEKHG4
NM_001129729.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.52

Publications

0 publications found

Variant links:

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]

PLEKHG4 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.20949244).

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PLEKHG4	NM_001129729.3	MANE Select	c.638C>G	p.Ala213Gly	missense	Exon 4 of 22	NP_001123201.1	A0A024R6X4
PLEKHG4	NM_001129727.3		c.638C>G	p.Ala213Gly	missense	Exon 5 of 23	NP_001123199.1	Q58EX7-1
PLEKHG4	NM_001129728.2		c.638C>G	p.Ala213Gly	missense	Exon 4 of 22	NP_001123200.1	A0A024R6X4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PLEKHG4	ENST00000379344.8	TSL:1 MANE Select	c.638C>G	p.Ala213Gly	missense	Exon 4 of 22	ENSP00000368649.3	Q58EX7-1
PLEKHG4	ENST00000450733.5	TSL:1	c.395C>G	p.Ala132Gly	missense	Exon 2 of 20	ENSP00000398030.1	Q58EX7-2
PLEKHG4	ENST00000393966.1	TSL:1	n.*223C>G		non_coding_transcript_exon	Exon 2 of 10	ENSP00000462601.1	Q58EX7-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000685

AC:

AN:

1460648

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

726710

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52214

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000809

AC:

AN:

1111992

Other (OTH)

AF:

0.0000166

AC:

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.47

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.045

Eigen

Benign

0.12

Eigen_PC

Uncertain

0.24

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.23

M_CAP

Benign

0.0055

MetaRNN

Benign

0.21

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.5

PhyloP100

1.5

PrimateAI

Benign

0.46

PROVEAN

Benign

-1.3

REVEL

Benign

0.040

Sift

Benign

0.46

Sift4G

Benign

0.28

Polyphen

0.058

Vest4

0.44

MutPred

0.38

Loss of stability (P = 0.0475)

MVP

0.33

MPC

0.27

ClinPred

0.75

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.10

gMVP

0.30

Mutation Taster

=86/14

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over