Genetic Variant NM_001129729.3:c.1235C>A (chr16-67282331-C-A) – 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.1235C>A(p.Thr412Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,284 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. T412I) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

PLEKHG4
NM_001129729.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.195

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=0.124326706).

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.1235C>A	p.Thr412Asn	missense	Exon 9 of 22	NP_001123201.1
PLEKHG4	NM_001129727.3		c.1235C>A	p.Thr412Asn	missense	Exon 10 of 23	NP_001123199.1
PLEKHG4	NM_001129728.2		c.1235C>A	p.Thr412Asn	missense	Exon 9 of 22	NP_001123200.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PLEKHG4	ENST00000379344.8	TSL:1 MANE Select	c.1235C>A	p.Thr412Asn	missense	Exon 9 of 22	ENSP00000368649.3
PLEKHG4	ENST00000450733.5	TSL:1	c.992C>A	p.Thr331Asn	missense	Exon 7 of 20	ENSP00000398030.1
PLEKHG4	ENST00000393966.1	TSL:1	n.*741C>A		non_coding_transcript_exon	Exon 6 of 10	ENSP00000462601.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460284

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726400

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33472

American (AMR)

AF:

0.00

AC:

AN:

44642

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26126

East Asian (EAS)

AF:

0.00

AC:

AN:

39678

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86220

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52308

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111708

Other (OTH)

AF:

0.00

AC:

AN:

60362

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.67

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.042

Eigen

Benign

-0.072

Eigen_PC

Benign

-0.086

FATHMM_MKL

Benign

0.094

LIST_S2

Benign

0.71

M_CAP

Benign

0.0068

MetaRNN

Benign

0.12

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.3

PhyloP100

0.20

PrimateAI

Benign

0.41

PROVEAN

Benign

-1.8

REVEL

Benign

0.050

Sift

Benign

0.21

Sift4G

Benign

0.16

Polyphen

0.84

Vest4

0.13

MutPred

0.20

Loss of glycosylation at T412 (P = 0.0465)

MVP

0.33

MPC

0.30

ClinPred

0.33

GERP RS

3.2

Varity_R

0.044

gMVP

0.12

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over