Genetic Variant NM_001129729.3:c.1574A>T (chr16-67284339-A-T) – 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.1574A>T(p.Asp525Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000062 in 1,613,138 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 𝑓 0.000040 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000064 ( 0 hom. )

Consequence

PLEKHG4
NM_001129729.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.793

Publications

36 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=0.084290594).

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
PLEKHG4	NM_001129729.3	MANE Select	c.1574A>T	p.Asp525Val	missense	Exon 12 of 22	NP_001123201.1
PLEKHG4	NM_001129727.3		c.1574A>T	p.Asp525Val	missense	Exon 13 of 23	NP_001123199.1
PLEKHG4	NM_001129728.2		c.1574A>T	p.Asp525Val	missense	Exon 12 of 22	NP_001123200.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PLEKHG4	ENST00000379344.8	TSL:1 MANE Select	c.1574A>T	p.Asp525Val	missense	Exon 12 of 22	ENSP00000368649.3
PLEKHG4	ENST00000450733.5	TSL:1	c.1331A>T	p.Asp444Val	missense	Exon 10 of 20	ENSP00000398030.1
PLEKHG4	ENST00000393966.1	TSL:1	n.*1080A>T		non_coding_transcript_exon	Exon 9 of 10	ENSP00000462601.1

Frequencies

GnomAD3 genomes

AF:

0.0000396

AC:

AN:

151618

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000737

Gnomad OTH

AF:

0.000481

GnomAD2 exomes

AF:

0.0000402

AC:

AN:

248826

AF XY:

0.0000296

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000580

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000535

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.0000643

AC:

AN:

1461520

Hom.:

Cov.:

AF XY:

0.0000825

AC XY:

AN XY:

727092

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33470

American (AMR)

AF:

0.0000671

AC:

AN:

44690

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26126

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.0000696

AC:

AN:

86244

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53288

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

0.0000693

AC:

AN:

1111878

Other (OTH)

AF:

0.000116

AC:

AN:

60376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

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

AF:

0.0000396

AC:

AN:

151618

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74022

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41314

American (AMR)

AF:

0.00

AC:

AN:

15214

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3462

East Asian (EAS)

AF:

0.00

AC:

AN:

5142

South Asian (SAS)

AF:

0.00

AC:

AN:

4810

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10518

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000737

AC:

AN:

67858

Other (OTH)

AF:

0.000481

AC:

AN:

2080

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.517

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.00000313

Hom.:

4865

ExAC

AF:

0.0000577

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.0000594

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.62

CADD

Benign

(source)

DANN

Benign

0.88

DEOGEN2

Benign

0.039

Eigen

Benign

-0.80

Eigen_PC

Benign

-0.67

FATHMM_MKL

Benign

0.16

LIST_S2

Benign

0.63

M_CAP

Benign

0.0043

MetaRNN

Benign

0.084

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

PhyloP100

0.79

PrimateAI

Benign

0.47

PROVEAN

Benign

-0.77

REVEL

Benign

0.088

Sift

Benign

0.13

Sift4G

Benign

0.31

Polyphen

0.0010

Vest4

0.29

MutPred

0.29

Loss of disorder (P = 0.0313)

MVP

0.27

MPC

0.37

ClinPred

0.031

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Varity_R

0.095

gMVP

0.21

Mutation Taster

=96/4

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over