17-8315267-G-T

Position:

chr17-8315267-G-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The ENST00000361926.8(ARHGEF15):c.1250G>T(p.Arg417Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0025 in 1,612,902 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R417S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0025 ( 2 hom., cov: 31)

Exomes 𝑓: 0.0025 ( 14 hom. )

Consequence

ARHGEF15
ENST00000361926.8 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 4.42

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 Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0074514747).

BP6

Variant 17-8315267-G-T is Benign according to our data. Variant chr17-8315267-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 412666.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARHGEF15	NM_173728.4 linkuse as main transcript	c.1250G>T	p.Arg417Leu	missense_variant	6/16	ENST00000361926.8	NP_776089.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
ARHGEF15	ENST00000361926.8 linkuse as main transcript	c.1250G>T	p.Arg417Leu	missense_variant	6/16	1	NM_173728.4	ENSP00000355026	P1
ARHGEF15	ENST00000421050.2 linkuse as main transcript	c.1250G>T	p.Arg417Leu	missense_variant	6/16	1		ENSP00000412505	P1
ARHGEF15	ENST00000647883.1 linkuse as main transcript	c.713G>T	p.Arg238Leu	missense_variant	3/13			ENSP00000498197
ARHGEF15	ENST00000578286.1 linkuse as main transcript	n.298G>T		non_coding_transcript_exon_variant	2/3	3

Frequencies

GnomAD3 genomes

AF:

0.00249

AC:

378

AN:

152070

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000338

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

Gnomad ASJ

AF:

0.00317

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.00528

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00418

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.00254

AC:

630

AN:

248104

Hom.:

AF XY:

0.00244

AC XY:

328

AN XY:

134674

show subpopulations

Gnomad AFR exome

AF:

0.000322

Gnomad AMR exome

AF:

0.000290

Gnomad ASJ exome

AF:

0.00210

Gnomad EAS exome

AF:

0.0000545

Gnomad SAS exome

AF:

0.000458

Gnomad FIN exome

AF:

0.00576

Gnomad NFE exome

AF:

0.00396

Gnomad OTH exome

AF:

0.00232

GnomAD4 exome

AF:

0.00250

AC:

3654

AN:

1460714

Hom.:

Cov.:

AF XY:

0.00256

AC XY:

1863

AN XY:

726668

show subpopulations

Gnomad4 AFR exome

AF:

0.000239

Gnomad4 AMR exome

AF:

0.000313

Gnomad4 ASJ exome

AF:

0.00161

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000545

Gnomad4 FIN exome

AF:

0.00482

Gnomad4 NFE exome

AF:

0.00285

Gnomad4 OTH exome

AF:

0.00191

GnomAD4 genome

AF:

0.00248

AC:

378

AN:

152188

Hom.:

Cov.:

AF XY:

0.00241

AC XY:

179

AN XY:

74422

show subpopulations

Gnomad4 AFR

AF:

0.000337

Gnomad4 AMR

AF:

0.000392

Gnomad4 ASJ

AF:

0.00317

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000621

Gnomad4 FIN

AF:

0.00528

Gnomad4 NFE

AF:

0.00418

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00343

Hom.:

Bravo

AF:

0.00145

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.000682

AC:

ESP6500EA

AF:

0.00268

AC:

ExAC

AF:

0.00286

AC:

347

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00289

EpiControl

AF:

0.00274

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2022	ARHGEF15: BP4, BS2 -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Early infantile epileptic encephalopathy with suppression bursts

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 22, 2024

- -

See cases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Nov 08, 2018

This variant was classified as: Benign. The following ACMG criteria were applied in classifying this variant: BS1,BS2. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.39

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.25

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.44

T;T;.

Eigen

Uncertain

0.66

Eigen_PC

Pathogenic

0.68

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.81

.;T;T

M_CAP

Benign

0.028

MetaRNN

Benign

0.0075

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.9

L;L;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.50

PROVEAN

Uncertain

-3.8

D;D;.

REVEL

Benign

0.24

Sift

Benign

0.032

D;D;.

Sift4G

Uncertain

0.010

D;D;.

Polyphen

0.99

D;D;.

Vest4

0.53

MVP

0.55

MPC

2.0

ClinPred

0.027

GERP RS

5.5

Varity_R

0.41

gMVP

0.74

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