Genetic Variant ARHGEF15:p.Pro73Ala (chr17-8312256-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_173728.4(ARHGEF15):c.217C>G(p.Pro73Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000000764 in 1,309,364 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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. P73S) has been classified as Benign.

Frequency

Genomes: not found (cov: 24)

Exomes 𝑓: 7.6e-7 ( 0 hom. )

Consequence

ARHGEF15
NM_173728.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.81

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: 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=0.21666953).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGEF15	NM_173728.4 link	c.217C>G	p.Pro73Ala	missense_variant	Exon 2 of 16	ENST00000361926.8	NP_776089.2	O94989A0A0S2Z547

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARHGEF15	ENST00000361926.8 link	c.217C>G	p.Pro73Ala	missense_variant	Exon 2 of 16	1	NM_173728.4	ENSP00000355026.3		O94989

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.64e-7

AC:

AN:

1309364

Hom.:

Cov.:

AF XY:

0.00000155

AC XY:

AN XY:

646818

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

29594

American (AMR)

AF:

0.00

AC:

AN:

36962

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18532

East Asian (EAS)

AF:

0.00

AC:

AN:

35320

South Asian (SAS)

AF:

0.0000131

AC:

AN:

76478

European-Finnish (FIN)

AF:

0.00

AC:

AN:

41944

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4934

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1014262

Other (OTH)

AF:

0.00

AC:

AN:

51338

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.775

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 v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.059

BayesDel_addAF

Benign

-0.095

BayesDel_noAF

Benign

-0.37

CADD

Benign

(source)

DANN

Benign

0.80

DEOGEN2

Benign

0.055

.;T;.;T

Eigen

Benign

-0.030

Eigen_PC

Benign

0.11

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.78

T;.;T;T

M_CAP

Benign

0.040

MetaRNN

Benign

0.22

T;T;T;T

MetaSVM

Benign

-0.78

MutationAssessor

Benign

1.0

.;L;.;L

PhyloP100

3.8

PrimateAI

Benign

0.37

PROVEAN

Benign

-1.1

.;N;.;N

REVEL

Benign

0.066

Sift

Uncertain

0.0020

.;D;.;D

Sift4G

Benign

0.088

T;T;T;T

Polyphen

0.32

.;B;.;B

Vest4

0.28

MutPred

0.17

Loss of relative solvent accessibility (P = 0.0071);Loss of relative solvent accessibility (P = 0.0071);Loss of relative solvent accessibility (P = 0.0071);Loss of relative solvent accessibility (P = 0.0071);

MVP

0.76

MPC

0.44

ClinPred

0.70

GERP RS

4.7

Varity_R

0.11

gMVP

0.14

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over