17-8312107-G-A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_173728.4(ARHGEF15):c.68G>A(p.Arg23His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000081 in 1,037,522 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R23C) has been classified as Benign.

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 6)

Exomes 𝑓: 0.000074 ( 0 hom. )

Consequence

ARHGEF15
NM_173728.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.33

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: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.14893398).

BS2

High AC in GnomAd4 at 11 Unknown,AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_173728.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGEF15	NM_173728.4	MANE Select	c.68G>A	p.Arg23His	missense	Exon 2 of 16	NP_776089.2
	ARHGEF15	NM_025014.2		c.68G>A	p.Arg23His	missense	Exon 2 of 16	NP_079290.1	O94989

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ARHGEF15	ENST00000361926.8	TSL:1 MANE Select	c.68G>A	p.Arg23His	missense	Exon 2 of 16	ENSP00000355026.3	O94989
ARHGEF15	ENST00000421050.2	TSL:1	c.68G>A	p.Arg23His	missense	Exon 2 of 16	ENSP00000412505.1	O94989
ARHGEF15	ENST00000852584.1		c.68G>A	p.Arg23His	missense	Exon 2 of 16	ENSP00000522643.1

Frequencies

GnomAD3 genomes

AF:

0.0000926

AC:

AN:

54008

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000180

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000208

AC:

AN:

144476

AF XY:

0.0000251

show subpopulations

Gnomad AFR exome

AF:

0.0000987

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000275

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000742

AC:

AN:

983488

Hom.:

Cov.:

AF XY:

0.0000672

AC XY:

AN XY:

476376

show subpopulations

African (AFR)

AF:

0.000196

AC:

AN:

20402

American (AMR)

AF:

0.00

AC:

AN:

19750

Ashkenazi Jewish (ASJ)

AF:

0.0000753

AC:

AN:

13272

East Asian (EAS)

AF:

0.00

AC:

AN:

21212

South Asian (SAS)

AF:

0.0000308

AC:

AN:

32436

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33920

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3774

European-Non Finnish (NFE)

AF:

0.0000836

AC:

AN:

801666

Other (OTH)

AF:

0.00

AC:

AN:

37056

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

AF:

0.000204

AC:

AN:

54034

Hom.:

Cov.:

AF XY:

0.000270

AC XY:

AN XY:

25928

show subpopulations

African (AFR)

AF:

0.000486

AC:

AN:

12334

American (AMR)

AF:

0.00

AC:

AN:

4430

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

1300

East Asian (EAS)

AF:

0.00

AC:

AN:

2140

South Asian (SAS)

AF:

0.00

AC:

AN:

1766

European-Finnish (FIN)

AF:

0.00

AC:

AN:

3188

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.000180

AC:

AN:

27702

Other (OTH)

AF:

0.00

AC:

AN:

692

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.515

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.000109

Hom.:

ExAC

AF:

0.00000824

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Developmental and epileptic encephalopathy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

0.00088

BayesDel_noAF

Benign

-0.24

CADD

Uncertain

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.050

Eigen

Benign

-0.15

Eigen_PC

Benign

0.022

FATHMM_MKL

Benign

0.26

LIST_S2

Benign

0.79

M_CAP

Benign

0.035

MetaRNN

Benign

0.15

MetaSVM

Benign

-1.0

MutationAssessor

Benign

2.0

PhyloP100

2.3

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-0.34

REVEL

Benign

0.094

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.047

Polyphen

0.035

Vest4

0.19

MVP

0.75

MPC

0.50

ClinPred

0.61

GERP RS

4.0

Varity_R

0.15

gMVP

0.25

Mutation Taster

=99/1

polymorphism

(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

Computational scores

Splicing

Publications

Other links and lift over