chr17-8312077-C-G

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.38C>G(p.Thr13Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000296 in 1,418,020 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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. T13M) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000076 ( 0 hom., cov: 23)

Exomes 𝑓: 0.000024 ( 0 hom. )

Consequence

ARHGEF15
NM_173728.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.31

Publications

0 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=0.13918671).

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.38C>G	p.Thr13Arg	missense	Exon 2 of 16	NP_776089.2
	ARHGEF15	NM_025014.2		c.38C>G	p.Thr13Arg	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.38C>G	p.Thr13Arg	missense	Exon 2 of 16	ENSP00000355026.3	O94989
ARHGEF15	ENST00000421050.2	TSL:1	c.38C>G	p.Thr13Arg	missense	Exon 2 of 16	ENSP00000412505.1	O94989
ARHGEF15	ENST00000852584.1		c.38C>G	p.Thr13Arg	missense	Exon 2 of 16	ENSP00000522643.1

Frequencies

GnomAD3 genomes

AF:

0.0000761

AC:

AN:

144640

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000257

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:

0.00

Gnomad OTH

AF:

0.000504

GnomAD2 exomes

AF:

0.0000379

AC:

AN:

211030

AF XY:

0.0000351

show subpopulations

Gnomad AFR exome

AF:

0.000457

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000642

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000243

AC:

AN:

1273380

Hom.:

Cov.:

AF XY:

0.0000205

AC XY:

AN XY:

633068

show subpopulations

African (AFR)

AF:

0.000802

AC:

AN:

26198

American (AMR)

AF:

0.00

AC:

AN:

32160

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

17154

East Asian (EAS)

AF:

0.0000835

AC:

AN:

23940

South Asian (SAS)

AF:

0.0000260

AC:

AN:

76858

European-Finnish (FIN)

AF:

0.00

AC:

AN:

41818

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4800

European-Non Finnish (NFE)

AF:

9.98e-7

AC:

AN:

1002176

Other (OTH)

AF:

0.000104

AC:

AN:

48276

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

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:

0.0000761

AC:

AN:

144640

Hom.:

Cov.:

AF XY:

0.0000854

AC XY:

AN XY:

70236

show subpopulations

African (AFR)

AF:

0.000257

AC:

AN:

38964

American (AMR)

AF:

0.00

AC:

AN:

14524

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3388

East Asian (EAS)

AF:

0.00

AC:

AN:

4664

South Asian (SAS)

AF:

0.00

AC:

AN:

4348

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9592

Middle Eastern (MID)

AF:

0.00

AC:

AN:

306

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

65982

Other (OTH)

AF:

0.000504

AC:

AN:

1986

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

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:

0.00

Hom.:

ExAC

AF:

0.0000330

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

0.17

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.25

CADD

Benign

(source)

DANN

Benign

0.87

DEOGEN2

Benign

0.058

Eigen

Benign

-0.098

Eigen_PC

Benign

-0.0066

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.73

M_CAP

Benign

0.055

MetaRNN

Benign

0.14

MetaSVM

Benign

-0.83

MutationAssessor

Benign

2.0

PhyloP100

2.3

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-0.74

REVEL

Benign

0.17

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.039

Polyphen

0.66

Vest4

0.38

MutPred

0.31

Loss of phosphorylation at T13 (P = 0.0024)

MVP

0.75

MPC

0.19

ClinPred

0.18

GERP RS

3.8

Varity_R

0.22

gMVP

0.39

Mutation Taster

=98/2

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

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