dbSNP rs35204656: ARHGEF15:p.Glu609Glu (chr17-8318617-A-G) – ACMG Classification: Benign (-19 pts)

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_173728.4(ARHGEF15):c.1827A>G(p.Glu609Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0159 in 1,613,772 control chromosomes in the GnomAD database, including 264 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.014 ( 24 hom., cov: 32)

Exomes 𝑓: 0.016 ( 240 hom. )

Consequence

ARHGEF15
NM_173728.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 1.34

Publications

4 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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.39).

BP6

Variant 17-8318617-A-G is Benign according to our data. Variant chr17-8318617-A-G is described in ClinVar as Benign. ClinVar VariationId is 412671.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=1.34 with no splicing effect.

BA1

GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0537 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGEF15	NM_173728.4 link	c.1827A>G	p.Glu609Glu	synonymous_variant	Exon 11 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.1827A>G	p.Glu609Glu	synonymous_variant	Exon 11 of 16	1	NM_173728.4	ENSP00000355026.3		O94989

Frequencies

GnomAD3 genomes

AF:

0.0142

AC:

2157

AN:

152114

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00398

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0191

Gnomad ASJ

AF:

0.0392

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.00455

Gnomad FIN

AF:

0.0237

Gnomad MID

AF:

0.0506

Gnomad NFE

AF:

0.0181

Gnomad OTH

AF:

0.0201

GnomAD2 exomes

AF:

0.0149

AC:

3740

AN:

251206

AF XY:

0.0150

show subpopulations

Gnomad AFR exome

AF:

0.00326

Gnomad AMR exome

AF:

0.0144

Gnomad ASJ exome

AF:

0.0430

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0200

Gnomad NFE exome

AF:

0.0180

Gnomad OTH exome

AF:

0.0216

GnomAD4 exome

AF:

0.0161

AC:

23544

AN:

1461540

Hom.:

240

Cov.:

AF XY:

0.0161

AC XY:

11688

AN XY:

727010

show subpopulations

African (AFR)

AF:

0.00568

AC:

190

AN:

33476

American (AMR)

AF:

0.0157

AC:

702

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.0450

AC:

1176

AN:

26126

East Asian (EAS)

AF:

0.00

AC:

AN:

39686

South Asian (SAS)

AF:

0.00546

AC:

471

AN:

86244

European-Finnish (FIN)

AF:

0.0185

AC:

986

AN:

53396

Middle Eastern (MID)

AF:

0.0588

AC:

339

AN:

5764

European-Non Finnish (NFE)

AF:

0.0167

AC:

18532

AN:

1111752

Other (OTH)

AF:

0.0190

AC:

1148

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

1386

2772

4157

5543

6929

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

688

1376

2064

2752

3440

<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:

0.0142

AC:

2155

AN:

152232

Hom.:

Cov.:

AF XY:

0.0142

AC XY:

1058

AN XY:

74424

show subpopulations

African (AFR)

AF:

0.00397

AC:

165

AN:

41556

American (AMR)

AF:

0.0190

AC:

291

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.0392

AC:

136

AN:

3466

East Asian (EAS)

AF:

0.000387

AC:

AN:

5172

South Asian (SAS)

AF:

0.00435

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0237

AC:

251

AN:

10602

Middle Eastern (MID)

AF:

0.0510

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0181

AC:

1231

AN:

68004

Other (OTH)

AF:

0.0204

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

109

218

326

435

544

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

130

<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:

0.0174

Hom.:

Bravo

AF:

0.0141

Asia WGS

AF:

0.00231

AC:

AN:

3478

EpiCase

AF:

0.0213

EpiControl

AF:

0.0210

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Developmental and epileptic encephalopathy

Benign:1

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.39

CADD

Benign

(source)

DANN

Benign

0.76

PhyloP100

1.3

Mutation Taster

=100/0

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