Genetic Variant ARHGEF15:p.Arg239Ser (chr17-8313035-C-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_025014.2(ARHGEF15):c.715C>A(p.Arg239Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,114 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 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. R239C) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

ARHGEF15
NM_025014.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.213

Publications

0 publications found

Variant links:

Genes affected

ARHGEF15 (HGNC:15590): (Rho guanine nucleotide exchange factor 15) Rho GTPases play a fundamental role in numerous cellular processes that are initiated by extracellular stimuli that work through G protein-coupled receptors. This gene encodes a protein that functions as a specific guanine nucleotide exchange factor for RhoA. It also interacts with ephrin A4 in vascular smooth muscle cells. Two alternatively spliced transcripts variants that encode the same protein have been found for this gene. [provided by RefSeq, Aug 2010]

ARHGEF15 Gene-Disease associations (from GenCC):

genetic developmental and epileptic encephalopathy
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
schizophrenia
Inheritance: Unknown Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)

ARHGEF15 links:

ENSG00000226871 (HGNC:):

ENSG00000226871 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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=0.045009524).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_025014.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGEF15	NM_173728.4	MANE Select	c.715C>A	p.Arg239Ser	missense	Exon 3 of 16	NP_776089.2
	ARHGEF15	NM_025014.2		c.715C>A	p.Arg239Ser	missense	Exon 3 of 16	NP_079290.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ARHGEF15	ENST00000361926.8	TSL:1 MANE Select	c.715C>A	p.Arg239Ser	missense	Exon 3 of 16	ENSP00000355026.3
ARHGEF15	ENST00000421050.2	TSL:1	c.715C>A	p.Arg239Ser	missense	Exon 3 of 16	ENSP00000412505.1
ARHGEF15	ENST00000852584.1		c.715C>A	p.Arg239Ser	missense	Exon 3 of 16	ENSP00000522643.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461114

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726886

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33474

American (AMR)

AF:

0.00

AC:

AN:

44698

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26090

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86232

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52988

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111802

Other (OTH)

AF:

0.0000166

AC:

AN:

60364

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.62

CADD

Benign

8.4

(source)

DANN

Benign

0.30

DEOGEN2

Benign

0.037

Eigen

Benign

-0.98

Eigen_PC

Benign

-0.88

FATHMM_MKL

Benign

0.32

LIST_S2

Benign

0.61

M_CAP

Benign

0.0044

MetaRNN

Benign

0.045

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.34

PhyloP100

0.21

PrimateAI

Benign

0.24

PROVEAN

Benign

-0.46

REVEL

Benign

0.013

Sift

Benign

0.63

Sift4G

Benign

0.70

Polyphen

0.0

Vest4

0.14

MutPred

0.39

Gain of phosphorylation at R239 (P = 0.0067)

MVP

0.26

MPC

0.094

ClinPred

0.019

GERP RS

1.8

Varity_R

0.20

gMVP

0.29

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over