5-140378-C-G

Position:

• chr5-140378-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_052909.5(PLEKHG4B):​c.1139C>G​(p.Ser380Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000714 in 1,400,052 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: PLEKHG4B NM_052909.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.333

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.115011156).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLEKHG4B	NM_052909.5	c.1139C>G	p.Ser380Cys	missense_variant	3/20	ENST00000637938.2	NP_443141.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLEKHG4B	ENST00000637938.2	c.1139C>G	p.Ser380Cys	missense_variant	3/20	5	NM_052909.5	ENSP00000490806.1
PLEKHG4B	ENST00000283426.11	c.71C>G	p.Ser24Cys	missense_variant	1/18	1		ENSP00000283426.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.14e-7 AC: 1 AN: 1400052 Hom.: 0 Cov.: 32 AF XY: 0.00000145 AC XY: 1 AN XY: 691068

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000173

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 01, 2024

The c.71C>G (p.S24C) alteration is located in exon 1 (coding exon 1) of the PLEKHG4B gene. This alteration results from a C to G substitution at nucleotide position 71, causing the serine (S) at amino acid position 24 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	9.8
DANN	Benign	0.92
DEOGEN2	Benign	0.013	.;T
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.72
FATHMM_MKL	Benign	0.033	N
LIST_S2	Benign	0.40	T;T
M_CAP	Benign	0.0022	T
MetaRNN	Benign	0.12	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	.;N
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-2.0	.;N
REVEL	Benign	0.055
Sift	Uncertain	0.010	.;D
Sift4G	Benign	0.064	.;T
Polyphen		0.88	.;P
Vest4		0.13
MutPred		0.20		.;Loss of phosphorylation at S24 (P = 0.0304);
MVP		0.20
MPC		0.20
ClinPred		0.16	T
GERP RS		2.7
Varity_R		0.12
gMVP		0.15

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-140493;