dbSNP rs138521691: ARHGEF15:p.Cys206Trp (chr17-8312938-C-G) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_173728.4(ARHGEF15):c.618C>G(p.Cys206Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000701 in 1,426,982 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. C206C) has been classified as Benign.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

ARHGEF15
NM_173728.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.309

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: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.349097).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGEF15	NM_173728.4 link	c.618C>G	p.Cys206Trp	missense_variant	Exon 3 of 16	ENST00000361926.8	NP_776089.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARHGEF15	ENST00000361926.8 link	c.618C>G	p.Cys206Trp	missense_variant	Exon 3 of 16	1	NM_173728.4	ENSP00000355026.3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.01e-7

AC:

AN:

1426982

Hom.:

Cov.:

AF XY:

0.00000142

AC XY:

AN XY:

705748

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33002

American (AMR)

AF:

0.00

AC:

AN:

42504

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23416

East Asian (EAS)

AF:

0.00

AC:

AN:

39468

South Asian (SAS)

AF:

0.00

AC:

AN:

79734

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49466

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5592

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1094810

Other (OTH)

AF:

0.0000170

AC:

AN:

58990

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.91

BayesDel_addAF

Benign

-0.061

BayesDel_noAF

Benign

-0.33

CADD

Benign

(source)

DANN

Benign

0.90

DEOGEN2

Benign

0.055

T;.;T

Eigen

Benign

-0.019

Eigen_PC

Benign

-0.073

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.37

.;T;T

M_CAP

Benign

0.065

MetaRNN

Benign

0.35

T;T;T

MetaSVM

Benign

-0.90

MutationAssessor

Benign

1.1

L;.;L

PhyloP100

-0.31

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-0.080

N;.;N

REVEL

Benign

0.21

Sift

Pathogenic

0.0

D;.;D

Sift4G

Uncertain

0.019

D;D;D

Polyphen

1.0

D;.;D

Vest4

0.64

MutPred

0.31

Loss of disorder (P = 0.0271);Loss of disorder (P = 0.0271);Loss of disorder (P = 0.0271);

MVP

0.81

MPC

0.53

ClinPred

0.89

GERP RS

2.3

PromoterAI

0.021

Neutral

(source)

Varity_R

0.63

gMVP

0.60

Mutation Taster

=95/5

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over