NM_173728.4:c.80G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_173728.4(ARHGEF15):c.80G>A(p.Arg27His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000616 in 1,379,258 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. R27P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00046 ( 0 hom., cov: 20)

Exomes 𝑓: 0.000031 ( 0 hom. )

Consequence

ARHGEF15
NM_173728.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 3.38

Publications

1 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 -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.030038357).

BS2

High AC in GnomAd4 at 46 Unknown,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGEF15	NM_173728.4 link	c.80G>A	p.Arg27His	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.80G>A	p.Arg27His	missense_variant	Exon 2 of 16	1	NM_173728.4	ENSP00000355026.3		O94989

Frequencies

GnomAD3 genomes

AF:

0.000457

AC:

AN:

100590

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000816

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00546

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:

0.00154

GnomAD2 exomes

AF:

0.0000494

AC:

AN:

182036

AF XY:

0.0000299

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000195

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000114

Gnomad OTH exome

AF:

0.00104

GnomAD4 exome

AF:

0.0000305

AC:

AN:

1278664

Hom.:

Cov.:

AF XY:

0.0000223

AC XY:

AN XY:

628156

show subpopulations

African (AFR)

AF:

0.0000360

AC:

AN:

27756

American (AMR)

AF:

0.000831

AC:

AN:

31294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

20878

East Asian (EAS)

AF:

0.00

AC:

AN:

31492

South Asian (SAS)

AF:

0.00

AC:

AN:

56636

European-Finnish (FIN)

AF:

0.00

AC:

AN:

45946

Middle Eastern (MID)

AF:

0.000398

AC:

AN:

5026

European-Non Finnish (NFE)

AF:

0.00000297

AC:

AN:

1008640

Other (OTH)

AF:

0.000137

AC:

AN:

50996

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.571

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:

0.000457

AC:

AN:

100594

Hom.:

Cov.:

AF XY:

0.000489

AC XY:

AN XY:

47044

show subpopulations

African (AFR)

AF:

0.0000815

AC:

AN:

24544

American (AMR)

AF:

0.00545

AC:

AN:

7704

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2722

East Asian (EAS)

AF:

0.00

AC:

AN:

3572

South Asian (SAS)

AF:

0.00

AC:

AN:

3260

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5006

Middle Eastern (MID)

AF:

0.00

AC:

AN:

112

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

51708

Other (OTH)

AF:

0.00153

AC:

AN:

1304

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.552

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:

0.0000454

Hom.:

Bravo

AF:

0.000797

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Developmental and epileptic encephalopathy

Uncertain:1

Jan 22, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 27 of the ARHGEF15 protein (p.Arg27His). This variant is present in population databases (rs199663714, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with ARHGEF15-related conditions. ClinVar contains an entry for this variant (Variation ID: 461440). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided

Uncertain:1

Jul 27, 2020

New York Genome Center

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.20

CADD

Pathogenic

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.056

.;T;.;T

Eigen

Uncertain

0.50

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.75

T;.;T;T

M_CAP

Uncertain

0.18

MetaRNN

Benign

0.030

T;T;T;T

MetaSVM

Benign

-0.38

MutationAssessor

Uncertain

2.0

.;M;.;M

PhyloP100

3.4

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-0.090

.;N;.;N

REVEL

Benign

0.24

Sift

Uncertain

0.0010

.;D;.;D

Sift4G

Benign

0.075

T;D;T;D

Polyphen

1.0

.;D;.;D

Vest4

0.39, 0.40

MVP

0.87

MPC

0.50

ClinPred

0.27

GERP RS

5.0

Varity_R

0.10

gMVP

0.29

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

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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