chr17-8319552-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000361926.8(ARHGEF15):c.2323C>T(p.Arg775Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0263 in 1,611,294 control chromosomes in the GnomAD database, including 694 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R775Q) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.022 ( 49 hom., cov: 32)

Exomes 𝑓: 0.027 ( 645 hom. )

Consequence

ARHGEF15
ENST00000361926.8 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 1.92

Publications

9 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0026908517).

BP6

Variant 17-8319552-C-T is Benign according to our data. Variant chr17-8319552-C-T is described in ClinVar as Benign. ClinVar VariationId is 242019.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0556 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000361926.8. 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.2323C>T	p.Arg775Trp	missense	Exon 15 of 16	NP_776089.2
	ARHGEF15	NM_025014.2		c.2323C>T	p.Arg775Trp	missense	Exon 15 of 16	NP_079290.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ARHGEF15	ENST00000361926.8	TSL:1 MANE Select	c.2323C>T	p.Arg775Trp	missense	Exon 15 of 16	ENSP00000355026.3
ARHGEF15	ENST00000421050.2	TSL:1	c.2323C>T	p.Arg775Trp	missense	Exon 15 of 16	ENSP00000412505.1
ARHGEF15	ENST00000647883.1		c.1786C>T	p.Arg596Trp	missense	Exon 12 of 13	ENSP00000498197.1

Frequencies

GnomAD3 genomes

AF:

0.0224

AC:

3402

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0201

Gnomad AMI

AF:

0.0658

Gnomad AMR

AF:

0.0177

Gnomad ASJ

AF:

0.0236

Gnomad EAS

AF:

0.000769

Gnomad SAS

AF:

0.0379

Gnomad FIN

AF:

0.00603

Gnomad MID

AF:

0.0696

Gnomad NFE

AF:

0.0267

Gnomad OTH

AF:

0.0306

GnomAD2 exomes

AF:

0.0234

AC:

5816

AN:

248436

AF XY:

0.0255

show subpopulations

Gnomad AFR exome

AF:

0.0192

Gnomad AMR exome

AF:

0.0150

Gnomad ASJ exome

AF:

0.0266

Gnomad EAS exome

AF:

0.0000549

Gnomad FIN exome

AF:

0.00802

Gnomad NFE exome

AF:

0.0282

Gnomad OTH exome

AF:

0.0268

GnomAD4 exome

AF:

0.0267

AC:

39010

AN:

1458980

Hom.:

645

Cov.:

AF XY:

0.0275

AC XY:

19990

AN XY:

725794

show subpopulations

African (AFR)

AF:

0.0221

AC:

734

AN:

33278

American (AMR)

AF:

0.0165

AC:

725

AN:

43986

Ashkenazi Jewish (ASJ)

AF:

0.0289

AC:

752

AN:

25976

East Asian (EAS)

AF:

0.0000757

AC:

AN:

39656

South Asian (SAS)

AF:

0.0416

AC:

3564

AN:

85752

European-Finnish (FIN)

AF:

0.00961

AC:

513

AN:

53382

Middle Eastern (MID)

AF:

0.0608

AC:

349

AN:

5736

European-Non Finnish (NFE)

AF:

0.0276

AC:

30686

AN:

1111002

Other (OTH)

AF:

0.0280

AC:

1684

AN:

60212

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

1882

3764

5645

7527

9409

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1162

2324

3486

4648

5810

<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:

0.0223

AC:

3403

AN:

152314

Hom.:

Cov.:

AF XY:

0.0215

AC XY:

1605

AN XY:

74484

show subpopulations

African (AFR)

AF:

0.0200

AC:

833

AN:

41558

American (AMR)

AF:

0.0177

AC:

271

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0236

AC:

AN:

3468

East Asian (EAS)

AF:

0.000771

AC:

AN:

5190

South Asian (SAS)

AF:

0.0382

AC:

184

AN:

4822

European-Finnish (FIN)

AF:

0.00603

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.0680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0268

AC:

1820

AN:

68034

Other (OTH)

AF:

0.0307

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

163

327

490

654

817

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

126

168

210

<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:

0.0252

Hom.:

158

Bravo

AF:

0.0234

TwinsUK

AF:

0.0245

AC:

ALSPAC

AF:

0.0280

AC:

108

ESP6500AA

AF:

0.0191

AC:

ESP6500EA

AF:

0.0253

AC:

218

ExAC

AF:

0.0247

AC:

2997

Asia WGS

AF:

0.0200

AC:

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Developmental and epileptic encephalopathy (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.38

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.21

Eigen

Benign

-0.055

Eigen_PC

Benign

-0.0059

FATHMM_MKL

Uncertain

0.76

LIST_S2

Benign

0.84

MetaRNN

Benign

0.0027

MetaSVM

Benign

-1.0

PhyloP100

1.9

PrimateAI

Benign

0.20

PROVEAN

Benign

-0.22

REVEL

Benign

0.13

Sift

Uncertain

0.020

Sift4G

Uncertain

0.017

Polyphen

0.99

Vest4

0.15

MPC

0.17

ClinPred

0.015

GERP RS

4.5

Varity_R

0.044

gMVP

0.53

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over