NM_173728.4:c.2366C>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_173728.4(ARHGEF15):c.2366C>A(p.Thr789Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000766 in 1,567,452 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0043 ( 6 hom., cov: 32)

Exomes 𝑓: 0.00038 ( 5 hom. )

Consequence

ARHGEF15
NM_173728.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.668

Publications

2 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: Benign. The variant received -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005372435).

BP6

Variant 17-8319595-C-A is Benign according to our data. Variant chr17-8319595-C-A is described in ClinVar as Benign. ClinVar VariationId is 412679.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 662 Unknown,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGEF15	NM_173728.4 link	c.2366C>A	p.Thr789Asn	missense_variant	Exon 15 of 16	ENST00000361926.8	NP_776089.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
ARHGEF15	ENST00000361926.8 link	c.2366C>A	p.Thr789Asn	missense_variant	Exon 15 of 16	1	NM_173728.4	ENSP00000355026.3
ARHGEF15	ENST00000421050.2 link	c.2366C>A	p.Thr789Asn	missense_variant	Exon 15 of 16	1		ENSP00000412505.1
ARHGEF15	ENST00000647883.1 link	c.1829C>A	p.Thr610Asn	missense_variant	Exon 12 of 13			ENSP00000498197.1
ENSG00000226871	ENST00000820533.1 link	n.100-816G>T		intron_variant	Intron 1 of 3

Frequencies

GnomAD3 genomes

AF:

0.00435

AC:

662

AN:

152146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0151

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00184

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:

0.0000588

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.00116

AC:

245

AN:

210850

AF XY:

0.000810

show subpopulations

Gnomad AFR exome

AF:

0.0145

Gnomad AMR exome

AF:

0.000665

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000196

Gnomad OTH exome

AF:

0.000415

GnomAD4 exome

AF:

0.000381

AC:

539

AN:

1415188

Hom.:

Cov.:

AF XY:

0.000326

AC XY:

229

AN XY:

703476

show subpopulations

African (AFR)

AF:

0.0143

AC:

440

AN:

30828

American (AMR)

AF:

0.000862

AC:

AN:

31338

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23488

East Asian (EAS)

AF:

0.00

AC:

AN:

38778

South Asian (SAS)

AF:

0.0000129

AC:

AN:

77634

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51880

Middle Eastern (MID)

AF:

0.000547

AC:

AN:

5484

European-Non Finnish (NFE)

AF:

0.0000118

AC:

AN:

1097620

Other (OTH)

AF:

0.000946

AC:

AN:

58138

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

124

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00435

AC:

662

AN:

152264

Hom.:

Cov.:

AF XY:

0.00419

AC XY:

312

AN XY:

74446

show subpopulations

African (AFR)

AF:

0.0150

AC:

625

AN:

41566

American (AMR)

AF:

0.00183

AC:

AN:

15264

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68028

Other (OTH)

AF:

0.00237

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

126

158

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00170

Hom.:

Bravo

AF:

0.00454

ESP6500AA

AF:

0.0143

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00128

AC:

155

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Developmental and epileptic encephalopathy

Benign:1

Jan 20, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

ARHGEF15-related disorder

Benign:1

Mar 27, 2019

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.061

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.62

CADD

Benign

(source)

DANN

Benign

0.89

DEOGEN2

Benign

0.18

T;T;.

Eigen

Benign

-0.53

Eigen_PC

Benign

-0.46

FATHMM_MKL

Benign

0.40

LIST_S2

Benign

0.55

.;T;T

MetaRNN

Benign

0.0054

T;T;T

MetaSVM

Benign

-0.90

PhyloP100

0.67

PrimateAI

Benign

0.34

PROVEAN

Benign

-2.0

N;N;.

REVEL

Benign

0.10

Sift

Benign

0.44

T;T;.

Sift4G

Benign

0.22

T;T;.

Polyphen

0.0010

B;B;.

Vest4

0.20

MVP

0.73

MPC

0.19

ClinPred

0.011

GERP RS

-1.1

Varity_R

0.038

gMVP

0.30

Mutation Taster

=96/4

polymorphism

(source)

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

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over