chr17-8312077-C-G

Position:

chr17-8312077-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_173728.4(ARHGEF15):c.38C>G(p.Thr13Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000296 in 1,418,020 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: 𝑓 0.000076 ( 0 hom., cov: 23)

Exomes 𝑓: 0.000024 ( 0 hom. )

Consequence

ARHGEF15
NM_173728.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.31

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.13918671).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARHGEF15	NM_173728.4 linkuse as main transcript	c.38C>G	p.Thr13Arg	missense_variant	2/16	ENST00000361926.8	NP_776089.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARHGEF15	ENST00000361926.8 linkuse as main transcript	c.38C>G	p.Thr13Arg	missense_variant	2/16	1	NM_173728.4	ENSP00000355026	P1

Frequencies

GnomAD3 genomes

AF:

0.0000761

AC:

AN:

144640

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000257

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:

0.00

Gnomad OTH

AF:

0.000504

GnomAD3 exomes

AF:

0.0000379

AC:

AN:

211030

Hom.:

AF XY:

0.0000351

AC XY:

AN XY:

113944

show subpopulations

Gnomad AFR exome

AF:

0.000457

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000642

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000243

AC:

AN:

1273380

Hom.:

Cov.:

AF XY:

0.0000205

AC XY:

AN XY:

633068

show subpopulations

Gnomad4 AFR exome

AF:

0.000802

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000835

Gnomad4 SAS exome

AF:

0.0000260

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.98e-7

Gnomad4 OTH exome

AF:

0.000104

GnomAD4 genome

AF:

0.0000761

AC:

AN:

144640

Hom.:

Cov.:

AF XY:

0.0000854

AC XY:

AN XY:

70236

show subpopulations

Gnomad4 AFR

AF:

0.000257

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000504

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Early infantile epileptic encephalopathy with suppression bursts

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 18, 2023

An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬† is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. ClinVar contains an entry for this variant (Variation ID: 648853). This variant has not been reported in the literature in individuals affected with ARHGEF15-related conditions. This variant is present in population databases (rs373751727, gnomAD 0.05%). This sequence change replaces threonine, which is neutral and polar, with arginine, which is basic and polar, at codon 13 of the ARHGEF15 protein (p.Thr13Arg). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.25

CADD

Benign

DANN

Benign

0.87

DEOGEN2

Benign

0.058

.;T;.;T

Eigen

Benign

-0.098

Eigen_PC

Benign

-0.0066

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.73

T;.;T;T

M_CAP

Benign

0.055

MetaRNN

Benign

0.14

T;T;T;T

MetaSVM

Benign

-0.83

MutationAssessor

Benign

2.0

.;M;.;M

MutationTaster

Benign

0.99

N;N

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-0.74

.;N;.;N

REVEL

Benign

0.17

Sift

Pathogenic

0.0

.;D;.;D

Sift4G

Uncertain

0.039

D;D;T;D

Polyphen

0.66

.;P;.;P

Vest4

0.38, 0.38

MutPred

0.31

Loss of phosphorylation at T13 (P = 0.0024);Loss of phosphorylation at T13 (P = 0.0024);Loss of phosphorylation at T13 (P = 0.0024);Loss of phosphorylation at T13 (P = 0.0024);

MVP

0.75

MPC

0.19

ClinPred

0.18

GERP RS

3.8

Varity_R

0.22

gMVP

0.39

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over