rs61742396

Variant names:

• chr6-150839980-G-A
• rs61742396
• NM_001029884.3:c.3242G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001029884.3(PLEKHG1):​c.3242G>A​(p.Gly1081Glu) variant causes a missense change. The variant allele was found at a frequency of 0.0408 in 1,613,938 control chromosomes in the GnomAD database, including 1,507 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.033 (95 hom., cov: 33)
  • Exomes 𝑓: 0.042 (1412 hom.)
• Consequence: PLEKHG1 NM_001029884.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.21
• Publications: 10 publications found

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

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0016655028).
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0517 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLEKHG1	NM_001029884.3	MANE Select	c.3242G>A	p.Gly1081Glu	missense	Exon 17 of 17	NP_001025055.1	Q9ULL1
	PLEKHG1	NM_001329798.2		c.3419G>A	p.Gly1140Glu	missense	Exon 16 of 16	NP_001316727.1
	PLEKHG1	NM_001329799.2		c.3362G>A	p.Gly1121Glu	missense	Exon 16 of 16	NP_001316728.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLEKHG1	ENST00000696526.1	MANE Select	c.3242G>A	p.Gly1081Glu	missense	Exon 17 of 17	ENSP00000512689.1	Q9ULL1
	PLEKHG1	ENST00000475490.1	TSL:1	n.1158-1055G>A		intron	N/A	ENSP00000433107.1	H0YD71
	PLEKHG1	ENST00000358517.6	TSL:5	c.3242G>A	p.Gly1081Glu	missense	Exon 16 of 16	ENSP00000351318.2	Q9ULL1

Frequencies

GnomAD3 genomes AF: 0.0329 AC: 5004 AN: 152130 Hom.: 92 Cov.: 33

Gnomad AFR AF: 0.0205

Gnomad AMI AF: 0.0175

Gnomad AMR AF: 0.0281

Gnomad ASJ AF: 0.0712

Gnomad EAS AF: 0.0197

Gnomad SAS AF: 0.0549

Gnomad FIN AF: 0.0151

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0418

Gnomad OTH AF: 0.0373

GnomAD2 exomes AF: 0.0358 AC: 8991 AN: 251328 AF XY: 0.0375

Gnomad AFR exome AF: 0.0218

Gnomad AMR exome AF: 0.0245

Gnomad ASJ exome AF: 0.0592

Gnomad EAS exome AF: 0.0204

Gnomad FIN exome AF: 0.0184

Gnomad NFE exome AF: 0.0401

Gnomad OTH exome AF: 0.0447

GnomAD4 exome AF: 0.0416 AC: 60793 AN: 1461690 Hom.: 1412 Cov.: 33 AF XY: 0.0421 AC XY: 30620 AN XY: 727162

African (AFR) AF: 0.0215 AC: 720 AN: 33480

American (AMR) AF: 0.0248 AC: 1111 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.0633 AC: 1654 AN: 26134

East Asian (EAS) AF: 0.0253 AC: 1003 AN: 39698

South Asian (SAS) AF: 0.0510 AC: 4400 AN: 86252

European-Finnish (FIN) AF: 0.0171 AC: 913 AN: 53416

Middle Eastern (MID) AF: 0.0567 AC: 327 AN: 5766

European-Non Finnish (NFE) AF: 0.0432 AC: 48082 AN: 1111840

Other (OTH) AF: 0.0428 AC: 2583 AN: 60392

GnomAD4 genome AF: 0.0330 AC: 5017 AN: 152248 Hom.: 95 Cov.: 33 AF XY: 0.0314 AC XY: 2339 AN XY: 74434

African (AFR) AF: 0.0205 AC: 852 AN: 41546

American (AMR) AF: 0.0280 AC: 428 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0712 AC: 247 AN: 3470

East Asian (EAS) AF: 0.0197 AC: 102 AN: 5172

South Asian (SAS) AF: 0.0551 AC: 266 AN: 4824

European-Finnish (FIN) AF: 0.0151 AC: 160 AN: 10608

Middle Eastern (MID) AF: 0.0544 AC: 16 AN: 294

European-Non Finnish (NFE) AF: 0.0417 AC: 2838 AN: 68008

Other (OTH) AF: 0.0436 AC: 92 AN: 2112

Alfa AF: 0.0400 Hom.: 466

Bravo AF: 0.0325

TwinsUK AF: 0.0472 AC: 175

ALSPAC AF: 0.0413 AC: 159

ESP6500AA AF: 0.0236 AC: 104

ESP6500EA AF: 0.0397 AC: 341

ExAC AF: 0.0360 AC: 4366

Asia WGS AF: 0.0590 AC: 205 AN: 3478

EpiCase AF: 0.0431

EpiControl AF: 0.0439

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	11
DANN	Benign	0.20
DEOGEN2	Benign	0.0014	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.76
FATHMM_MKL	Benign	0.099	N
LIST_S2	Benign	0.35	T
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-2.2	N
PhyloP100		5.2
PrimateAI	Benign	0.39	T
PROVEAN	Benign	1.8	N
REVEL	Benign	0.14
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.074
ClinPred		0.0050	T
GERP RS		5.8
Varity_R		0.042
gMVP		0.10
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs61742396; hg19: chr6-151161116;