chr5-140546-G-T

Variant names:

• chr5-140546-G-T
• rs1338982037
• NM_052909.5:c.1307G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_052909.5(PLEKHG4B):​c.1307G>T​(p.Arg436Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000207 in 1,451,838 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 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. R436K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: PLEKHG4B NM_052909.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.39
• Publications: 0 publications found

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

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=0.11987957).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_052909.5. 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
	PLEKHG4B	NM_052909.5	MANE Select	c.1307G>T	p.Arg436Ile	missense	Exon 3 of 20	NP_443141.4	Q96PX9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLEKHG4B	ENST00000637938.2	TSL:5 MANE Select	c.1307G>T	p.Arg436Ile	missense	Exon 3 of 20	ENSP00000490806.1	Q96PX9
	PLEKHG4B	ENST00000283426.11	TSL:1	c.239G>T	p.Arg80Ile	missense	Exon 1 of 18	ENSP00000283426.6	A0AAK2PKJ8
	PLEKHG4B	ENST00000924300.1		c.1307G>T	p.Arg436Ile	missense	Exon 3 of 20	ENSP00000594359.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000207 AC: 3 AN: 1451838 Hom.: 0 Cov.: 34 AF XY: 0.00000139 AC XY: 1 AN XY: 721416

African (AFR) AF: 0.00 AC: 0 AN: 33334

American (AMR) AF: 0.00 AC: 0 AN: 43338

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25766

East Asian (EAS) AF: 0.00 AC: 0 AN: 39414

South Asian (SAS) AF: 0.00 AC: 0 AN: 84830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51566

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.00000271 AC: 3 AN: 1107862

Other (OTH) AF: 0.00 AC: 0 AN: 59974

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	18
DANN	Benign	0.94
DEOGEN2	Benign	0.015	T
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.0030	T
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		1.4
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.058
Sift	Uncertain	0.028	D
Sift4G	Benign	0.086	T
Polyphen		0.99	D
Vest4		0.28
MutPred		0.17		Loss of glycosylation at P78 (P = 0.0582)
MVP		0.26
MPC		0.58
ClinPred		0.57	D
GERP RS		1.7
PromoterAI		0.0058	Neutral
Varity_R		0.15
gMVP		0.50
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs1338982037; hg19: chr5-140661;