Genetic Variant ARHGEF15:p.Thr13Pro (chr17-8312076-A-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_173728.4(ARHGEF15):c.37A>C(p.Thr13Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 0.0011 ( 0 hom., cov: 16)

Exomes 𝑓: 0.00053 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

ARHGEF15
NM_173728.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.269

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: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.16974118).

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.37A>C	p.Thr13Pro	missense	Exon 2 of 16	NP_776089.2
	ARHGEF15	NM_025014.2		c.37A>C	p.Thr13Pro	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.37A>C	p.Thr13Pro	missense	Exon 2 of 16	ENSP00000355026.3	O94989
ARHGEF15	ENST00000421050.2	TSL:1	c.37A>C	p.Thr13Pro	missense	Exon 2 of 16	ENSP00000412505.1	O94989
ARHGEF15	ENST00000852584.1		c.37A>C	p.Thr13Pro	missense	Exon 2 of 16	ENSP00000522643.1

Frequencies

GnomAD3 genomes

AF:

0.00109

AC:

AN:

62216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00115

Gnomad AMI

AF:

0.00244

Gnomad AMR

AF:

0.000612

Gnomad ASJ

AF:

0.00191

Gnomad EAS

AF:

0.00517

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000539

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00103

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000489

AC:

AN:

155300

AF XY:

0.000447

show subpopulations

Gnomad AFR exome

AF:

0.000367

Gnomad AMR exome

AF:

0.000483

Gnomad ASJ exome

AF:

0.000439

Gnomad EAS exome

AF:

0.000657

Gnomad FIN exome

AF:

0.000519

Gnomad NFE exome

AF:

0.000272

Gnomad OTH exome

AF:

0.00203

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000527

AC:

530

AN:

1006534

Hom.:

Cov.:

AF XY:

0.000563

AC XY:

279

AN XY:

495326

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.000404

AC:

AN:

19786

American (AMR)

AF:

0.00110

AC:

AN:

21874

Ashkenazi Jewish (ASJ)

AF:

0.00121

AC:

AN:

11596

East Asian (EAS)

AF:

0.000739

AC:

AN:

14882

South Asian (SAS)

AF:

0.00202

AC:

104

AN:

51388

European-Finnish (FIN)

AF:

0.00122

AC:

AN:

29440

Middle Eastern (MID)

AF:

0.000533

AC:

AN:

3752

European-Non Finnish (NFE)

AF:

0.000362

AC:

296

AN:

817628

Other (OTH)

AF:

0.000967

AC:

AN:

36188

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.250

Heterozygous variant carriers

144

216

288

360

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

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00109

AC:

AN:

62314

Hom.:

Cov.:

AF XY:

0.000949

AC XY:

AN XY:

30572

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00115

AC:

AN:

15692

American (AMR)

AF:

0.000611

AC:

AN:

6550

Ashkenazi Jewish (ASJ)

AF:

0.00191

AC:

AN:

1570

East Asian (EAS)

AF:

0.00517

AC:

AN:

1742

South Asian (SAS)

AF:

0.00

AC:

AN:

1608

European-Finnish (FIN)

AF:

0.000539

AC:

AN:

3708

Middle Eastern (MID)

AF:

0.00

AC:

AN:

118

European-Non Finnish (NFE)

AF:

0.00103

AC:

AN:

30080

Other (OTH)

AF:

0.00

AC:

AN:

836

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.249

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:

0.00150

Hom.:

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

0.057

BayesDel_addAF

Benign

-0.038

BayesDel_noAF

Benign

-0.29

CADD

Benign

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.043

Eigen

Benign

-0.13

Eigen_PC

Benign

-0.058

FATHMM_MKL

Benign

0.58

LIST_S2

Benign

0.59

M_CAP

Benign

0.022

MetaRNN

Benign

0.17

MetaSVM

Benign

-0.91

MutationAssessor

Benign

2.0

PhyloP100

0.27

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-0.47

REVEL

Benign

0.091

Sift

Uncertain

0.0010

Sift4G

Benign

0.25

Polyphen

0.61

Vest4

0.30

MVP

0.76

MPC

0.17

ClinPred

0.062

GERP RS

2.4

Varity_R

0.19

gMVP

0.18

Mutation Taster

=97/3

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