Genetic Variant NM_001029884.3:c.-99+32848G>C (chr6-150683634-G-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001029884.3(PLEKHG1):c.-99+32848G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0887 in 401,208 control chromosomes in the GnomAD database, including 1,938 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.087 ( 650 hom., cov: 31)

Exomes 𝑓: 0.090 ( 1288 hom. )

Consequence

PLEKHG1
NM_001029884.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.579

Publications

27 publications found

Variant links:

Genes affected

PLEKHG1 (HGNC:20884): (pleckstrin homology and RhoGEF domain containing G1) Predicted to enable guanyl-nucleotide exchange factor activity. Predicted to be involved in regulation of small GTPase mediated signal transduction. Located in nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

PLEKHG1 Gene-Disease associations (from GenCC):

periventricular leukomalacia
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

PLEKHG1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.15 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001029884.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
PLEKHG1	NM_001029884.3	MANE Select	c.-99+32848G>C	intron	N/A	NP_001025055.1
PLEKHG1	NM_001329799.2		c.23-49950G>C	intron	N/A	NP_001316728.1
PLEKHG1	NM_001329804.2		c.-99+32848G>C	intron	N/A	NP_001316733.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
PLEKHG1	ENST00000696526.1	MANE Select	c.-99+32848G>C	intron	N/A	ENSP00000512689.1
PLEKHG1	ENST00000644968.1		c.-347G>C	5_prime_UTR	Exon 1 of 16	ENSP00000496254.1
PLEKHG1	ENST00000367326.1	TSL:3	c.-99+32848G>C	intron	N/A	ENSP00000356295.1

Frequencies

GnomAD3 genomes

AF:

0.0865

AC:

13142

AN:

151998

Hom.:

641

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0997

Gnomad AMI

AF:

0.0978

Gnomad AMR

AF:

0.137

Gnomad ASJ

AF:

0.0473

Gnomad EAS

AF:

0.0655

Gnomad SAS

AF:

0.160

Gnomad FIN

AF:

0.0801

Gnomad MID

AF:

0.127

Gnomad NFE

AF:

0.0661

Gnomad OTH

AF:

0.0885

GnomAD4 exome

AF:

0.0900

AC:

22429

AN:

249092

Hom.:

1288

Cov.:

AF XY:

0.0976

AC XY:

13100

AN XY:

134290

show subpopulations

African (AFR)

AF:

0.107

AC:

653

AN:

6116

American (AMR)

AF:

0.160

AC:

1629

AN:

10204

Ashkenazi Jewish (ASJ)

AF:

0.0487

AC:

230

AN:

4724

East Asian (EAS)

AF:

0.0708

AC:

531

AN:

7496

South Asian (SAS)

AF:

0.164

AC:

6936

AN:

42252

European-Finnish (FIN)

AF:

0.0751

AC:

650

AN:

8660

Middle Eastern (MID)

AF:

0.112

AC:

266

AN:

2366

European-Non Finnish (NFE)

AF:

0.0679

AC:

10599

AN:

156072

Other (OTH)

AF:

0.0835

AC:

935

AN:

11202

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

941

1882

2824

3765

4706

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

256

512

768

1024

1280

<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:

0.0865

AC:

13163

AN:

152116

Hom.:

650

Cov.:

AF XY:

0.0886

AC XY:

6589

AN XY:

74358

show subpopulations

African (AFR)

AF:

0.0996

AC:

4133

AN:

41478

American (AMR)

AF:

0.138

AC:

2105

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.0473

AC:

164

AN:

3468

East Asian (EAS)

AF:

0.0651

AC:

336

AN:

5164

South Asian (SAS)

AF:

0.160

AC:

769

AN:

4812

European-Finnish (FIN)

AF:

0.0801

AC:

848

AN:

10590

Middle Eastern (MID)

AF:

0.126

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0661

AC:

4497

AN:

68010

Other (OTH)

AF:

0.0876

AC:

185

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

597

1194

1791

2388

2985

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

154

308

462

616

770

<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:

0.0764

Hom.:

Bravo

AF:

0.0896

Asia WGS

AF:

0.123

AC:

427

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

7.2

(source)

DANN

Benign

0.71

PhyloP100

0.58

PromoterAI

0.051

Neutral

(source)

Mutation Taster

=97/3

polymorphism (auto)

(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