rs770616036

Variant names:

• chr14-64727872-C-T
• rs770616036
• NM_001308147.2:c.241C>T

Your query was ambiguous. Multiple possible variants found:

• chr14-64727872-C-T
• chr14-64727872-C-A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001308147.2(PLEKHG3):​c.241C>T​(p.Arg81Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000291 in 1,613,194 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000030 (0 hom.)
• Consequence: PLEKHG3 NM_001308147.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.08
• Publications: 0 publications found

Genes affected

PLEKHG3 (HGNC:20364): (pleckstrin homology and RhoGEF domain containing G3) Predicted to enable guanyl-nucleotide exchange factor activity. Predicted to be involved in regulation of small GTPase mediated signal transduction. Predicted to be located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.39225256).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001308147.2. 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
	PLEKHG3	NM_001308147.2	MANE Select	c.241C>T	p.Arg81Trp	missense	Exon 2 of 17	NP_001295076.1	A1L390-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLEKHG3	ENST00000247226.13	TSL:1 MANE Select	c.241C>T	p.Arg81Trp	missense	Exon 2 of 17	ENSP00000247226.8	A1L390-1
	PLEKHG3	ENST00000634379.2	TSL:1	c.304C>T	p.Arg102Trp	missense	Exon 2 of 17	ENSP00000489373.2	A0A0U1RR71
	PLEKHG3	ENST00000471182.7	TSL:5	c.241C>T	p.Arg81Trp	missense	Exon 1 of 17	ENSP00000450945.2	A0A8C8NWT4

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152236 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000241 AC: 6 AN: 249278 AF XY: 0.0000222

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000267

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000301 AC: 44 AN: 1460958 Hom.: 0 Cov.: 32 AF XY: 0.0000344 AC XY: 25 AN XY: 726720

African (AFR) AF: 0.0000299 AC: 1 AN: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39668

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86208

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53118

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5764

European-Non Finnish (NFE) AF: 0.0000333 AC: 37 AN: 1111538

Other (OTH) AF: 0.0000166 AC: 1 AN: 60370

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152236 Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3 AN XY: 74372

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41462

American (AMR) AF: 0.00 AC: 0 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68040

Other (OTH) AF: 0.00 AC: 0 AN: 2094

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00131091), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0000403 Hom.: 0

Bravo AF: 0.0000302

ExAC AF: 0.0000494 AC: 6

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.072	T
Eigen	Benign	0.14
Eigen_PC	Benign	-0.0040
FATHMM_MKL	Benign	0.37	N
LIST_S2	Benign	0.84	T
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.39	T
MetaSVM	Uncertain	-0.017	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		1.1
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-4.3	D
REVEL	Benign	0.20
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.0060	D
Polyphen		1.0	D
Vest4		0.22
MutPred		0.46		Loss of disorder (P = 0.0143)
MVP		0.65
MPC		0.15
ClinPred		0.74	D
GERP RS		4.5
PromoterAI		-0.0014	Neutral
Varity_R		0.22
gMVP		0.55
Mutation Taster		=90/10	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs770616036; hg19: chr14-65194590;