5-140449-C-T

Variant names:

• chr5-140449-C-T
• rs950170891
• NM_052909.5:c.1210C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_052909.5(PLEKHG4B):​c.1210C>T​(p.Pro404Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000701 in 1,427,270 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 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. P404T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: PLEKHG4B NM_052909.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.913
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06368032).

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.1210C>T	p.Pro404Ser	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.1210C>T	p.Pro404Ser	missense	Exon 3 of 20	ENSP00000490806.1	Q96PX9
	PLEKHG4B	ENST00000283426.11	TSL:1	c.142C>T	p.Pro48Ser	missense	Exon 1 of 18	ENSP00000283426.6	A0AAK2PKJ8
	PLEKHG4B	ENST00000924300.1		c.1210C>T	p.Pro404Ser	missense	Exon 3 of 20	ENSP00000594359.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.01e-7 AC: 1 AN: 1427270 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 706914

African (AFR) AF: 0.00 AC: 0 AN: 32626

American (AMR) AF: 0.00 AC: 0 AN: 39834

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25270

East Asian (EAS) AF: 0.00 AC: 0 AN: 37868

South Asian (SAS) AF: 0.00 AC: 0 AN: 81802

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49928

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5712

European-Non Finnish (NFE) AF: 9.13e-7 AC: 1 AN: 1095226

Other (OTH) AF: 0.00 AC: 0 AN: 59004

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	0.045
DANN	Benign	0.41
DEOGEN2	Benign	0.0049	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.015	N
LIST_S2	Benign	0.42	T
M_CAP	Benign	0.0046	T
MetaRNN	Benign	0.064	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.91
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.020
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.45	T
Polyphen		0.010	B
Vest4		0.040
MutPred		0.21		Gain of phosphorylation at P48 (P = 0.0103)
MVP		0.061
MPC		0.083
ClinPred		0.064	T
GERP RS		1.6
PromoterAI		0.00070	Neutral
Varity_R		0.053
gMVP		0.16
Mutation Taster		=100/0	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: rs950170891; hg19: chr5-140564; COSMIC: COSV104623565; COSMIC: COSV104623565;