5-143134-G-C

Variant names:

• chr5-143134-G-C
• rs115149634
• NM_052909.5:c.1565G>C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_052909.5(PLEKHG4B):​c.1565G>C​(p.Arg522Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00171 in 1,612,610 control chromosomes in the GnomAD database, including 19 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R522Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0031 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0016 (17 hom.)
• Consequence: PLEKHG4B NM_052909.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.148

Genes affected

PLEKHG4B (HGNC:29399): (pleckstrin homology and RhoGEF domain containing G4B) This gene encodes a large protein that contains a pleckstrin homology domain and may function as a guanine nucleotide exchange factor. [provided by RefSeq, May 2017]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0036451817).
• BS2: High Homozygotes in GnomAd4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLEKHG4B	NM_052909.5	c.1565G>C	p.Arg522Pro	missense_variant	Exon 4 of 20	ENST00000637938.2	NP_443141.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLEKHG4B	ENST00000637938.2	c.1565G>C	p.Arg522Pro	missense_variant	Exon 4 of 20	5	NM_052909.5	ENSP00000490806.1
PLEKHG4B	ENST00000283426.11	c.497G>C	p.Arg166Pro	missense_variant	Exon 2 of 18	1		ENSP00000283426.6
PLEKHG4B	ENST00000502646.1	c.239G>C	p.Arg80Pro	missense_variant	Exon 2 of 9	1		ENSP00000422493.1

Frequencies

GnomAD3 genomes AF: 0.00307 AC: 467 AN: 152154 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00558

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00294

Gnomad ASJ AF: 0.0352

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000794

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00274 AC: 683 AN: 249146 Hom.: 6 AF XY: 0.00239 AC XY: 323 AN XY: 135322

Gnomad AFR exome AF: 0.00671

Gnomad AMR exome AF: 0.00341

Gnomad ASJ exome AF: 0.0302

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.0000469

Gnomad NFE exome AF: 0.00100

Gnomad OTH exome AF: 0.00559

GnomAD4 exome AF: 0.00157 AC: 2289 AN: 1460338 Hom.: 17 Cov.: 33 AF XY: 0.00157 AC XY: 1137 AN XY: 726498

Gnomad4 AFR exome AF: 0.00597

Gnomad4 AMR exome AF: 0.00394

Gnomad4 ASJ exome AF: 0.0289

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000232

Gnomad4 FIN exome AF: 0.0000963

Gnomad4 NFE exome AF: 0.000779

Gnomad4 OTH exome AF: 0.00386

GnomAD4 genome AF: 0.00307 AC: 467 AN: 152272 Hom.: 2 Cov.: 33 AF XY: 0.00299 AC XY: 223 AN XY: 74458

Gnomad4 AFR AF: 0.00558

Gnomad4 AMR AF: 0.00294

Gnomad4 ASJ AF: 0.0352

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000794

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00402 Hom.: 2

Bravo AF: 0.00379

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.00658 AC: 29

ESP6500EA AF: 0.00221 AC: 19

ExAC AF: 0.00238 AC: 289

EpiCase AF: 0.00136

EpiControl AF: 0.00207

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	2.1
DANN	Benign	0.51
DEOGEN2	Benign	0.0046	.;T;T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.024	N
LIST_S2	Benign	0.34	T;T;T
M_CAP	Benign	0.0018	T
MetaRNN	Benign	0.0036	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	.;N;.
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.35	.;N;N
REVEL	Benign	0.0010
Sift	Benign	0.18	.;T;T
Sift4G	Benign	0.30	.;T;T
Polyphen		0.11	.;B;.
Vest4		0.065
MVP		0.040
MPC		0.12
ClinPred		0.00064	T
GERP RS		-2.4
Varity_R		0.072
gMVP		0.22

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

Publications

LitVar

Other links and lift over

dbSNP: rs115149634; hg19: chr5-143249; COSMIC: COSV99360161; COSMIC: COSV99360161;