17-8312256-C-T

Variant names:

Variant summary

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

The NM_173728.4(ARHGEF15):c.217C>T(p.Pro73Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00289 in 1,454,904 control chromosomes in the GnomAD database, including 102 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.014 ( 53 hom., cov: 24)

Exomes 𝑓: 0.0016 ( 49 hom. )

Consequence

ARHGEF15
NM_173728.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 3.81

Publications

3 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=0.0029857159).

BP6

Variant 17-8312256-C-T is Benign according to our data. Variant chr17-8312256-C-T is described in ClinVar as Benign. ClinVar VariationId is 412670.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.057 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGEF15	NM_173728.4 link	c.217C>T	p.Pro73Ser	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>T	p.Pro73Ser	missense_variant	Exon 2 of 16	1	NM_173728.4	ENSP00000355026.3		O94989

Frequencies

GnomAD3 genomes

AF:

0.0143

AC:

2086

AN:

145418

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0501

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00454

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00325

Gnomad NFE

AF:

0.000121

Gnomad OTH

AF:

0.0120

GnomAD2 exomes

AF:

0.00407

AC:

853

AN:

209654

AF XY:

0.00320

show subpopulations

Gnomad AFR exome

AF:

0.0494

Gnomad AMR exome

AF:

0.00192

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000158

Gnomad OTH exome

AF:

0.00161

GnomAD4 exome

AF:

0.00162

AC:

2115

AN:

1309364

Hom.:

Cov.:

AF XY:

0.00139

AC XY:

896

AN XY:

646818

show subpopulations

African (AFR)

AF:

0.0593

AC:

1755

AN:

29594

American (AMR)

AF:

0.00252

AC:

AN:

36962

Ashkenazi Jewish (ASJ)

AF:

0.0000540

AC:

AN:

18532

East Asian (EAS)

AF:

0.0000283

AC:

AN:

35320

South Asian (SAS)

AF:

0.0000785

AC:

AN:

76478

European-Finnish (FIN)

AF:

0.00

AC:

AN:

41944

Middle Eastern (MID)

AF:

0.00203

AC:

AN:

4934

European-Non Finnish (NFE)

AF:

0.000101

AC:

102

AN:

1014262

Other (OTH)

AF:

0.00286

AC:

147

AN:

51338

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.617

Heterozygous variant carriers

196

293

391

489

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

180

240

300

<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:

0.0144

AC:

2089

AN:

145540

Hom.:

Cov.:

AF XY:

0.0138

AC XY:

978

AN XY:

70734

show subpopulations

African (AFR)

AF:

0.0500

AC:

1990

AN:

39796

American (AMR)

AF:

0.00453

AC:

AN:

14554

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3378

East Asian (EAS)

AF:

0.00

AC:

AN:

4910

South Asian (SAS)

AF:

0.00

AC:

AN:

4278

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9580

Middle Eastern (MID)

AF:

0.00350

AC:

AN:

286

European-Non Finnish (NFE)

AF:

0.000121

AC:

AN:

65844

Other (OTH)

AF:

0.0118

AC:

AN:

2030

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.571

Heterozygous variant carriers

172

258

344

430

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

<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:

0.00592

Hom.:

Bravo

AF:

0.0159

ESP6500AA

AF:

0.0433

AC:

191

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00437

AC:

530

Asia WGS

AF:

0.00144

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Developmental and epileptic encephalopathy

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

0.085

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.46

CADD

Uncertain

(source)

DANN

Benign

0.91

DEOGEN2

Benign

0.055

.;T;.;T

Eigen

Benign

-0.023

Eigen_PC

Benign

0.12

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.80

T;.;T;T

MetaRNN

Benign

0.0030

T;T;T;T

MetaSVM

Benign

-0.90

MutationAssessor

Benign

1.0

.;L;.;L

PhyloP100

3.8

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.72

.;N;.;N

REVEL

Benign

0.11

Sift

Uncertain

0.0020

.;D;.;D

Sift4G

Uncertain

0.044

D;T;T;T

Polyphen

0.32

.;B;.;B

Vest4

0.30, 0.29

MVP

0.76

MPC

0.46

ClinPred

0.019

GERP RS

4.7

Varity_R

0.12

gMVP

0.19

Mutation Taster

=97/3

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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