rs115597604

Variant names:

• chr17-8320961-T-C
• rs115597604
• NM_173728.4:c.2494T>C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_025014.2(ARHGEF15):​c.2494T>C​(p.Ser832Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000403 in 1,613,936 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S832F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0019 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00025 (4 hom.)
• Consequence: ARHGEF15 NM_025014.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 1.66
• Publications: 2 publications found

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)

ENSG00000226871 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.014302611).
• BP6: Variant 17-8320961-T-C is Benign according to our data. Variant chr17-8320961-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 461434.
• BS2: High AC in GnomAd4 at 291 Unknown,AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_025014.2. 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.2494T>C	p.Ser832Pro	missense	Exon 16 of 16	NP_776089.2
	ARHGEF15	NM_025014.2		c.2494T>C	p.Ser832Pro	missense	Exon 16 of 16	NP_079290.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGEF15	ENST00000361926.8	TSL:1 MANE Select	c.2494T>C	p.Ser832Pro	missense	Exon 16 of 16	ENSP00000355026.3
	ARHGEF15	ENST00000421050.2	TSL:1	c.2494T>C	p.Ser832Pro	missense	Exon 16 of 16	ENSP00000412505.1
	ARHGEF15	ENST00000852584.1		c.2539T>C	p.Ser847Pro	missense	Exon 16 of 16	ENSP00000522643.1

Frequencies

GnomAD3 genomes AF: 0.00189 AC: 288 AN: 152076 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00642

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

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: 0.0000147

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.000517 AC: 130 AN: 251432 AF XY: 0.000324

Gnomad AFR exome AF: 0.00658

Gnomad AMR exome AF: 0.000434

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000246 AC: 359 AN: 1461742 Hom.: 4 Cov.: 33 AF XY: 0.000219 AC XY: 159 AN XY: 727176

African (AFR) AF: 0.00729 AC: 244 AN: 33478

American (AMR) AF: 0.000447 AC: 20 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53392

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.0000234 AC: 26 AN: 1111906

Other (OTH) AF: 0.00111 AC: 67 AN: 60384

GnomAD4 genome AF: 0.00191 AC: 291 AN: 152194 Hom.: 1 Cov.: 32 AF XY: 0.00179 AC XY: 133 AN XY: 74406

African (AFR) AF: 0.00648 AC: 269 AN: 41530

American (AMR) AF: 0.00118 AC: 18 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67992

Other (OTH) AF: 0.00142 AC: 3 AN: 2110

Alfa AF: 0.000729 Hom.: 0

Bravo AF: 0.00229

ESP6500AA AF: 0.00477 AC: 21

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000593 AC: 72

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Developmental and epileptic encephalopathy (1)
-	-	1	not provided (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.11
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.065	T
Eigen	Benign	-0.039
Eigen_PC	Benign	-0.087
FATHMM_MKL	Benign	0.53	D
LIST_S2	Benign	0.65	T
MetaRNN	Benign	0.014	T
MetaSVM	Benign	-0.75	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		1.7
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.84	N
REVEL	Benign	0.29
Sift	Uncertain	0.010	D
Sift4G	Benign	0.18	T
Polyphen		0.99	D
Vest4		0.23
MVP		0.78
MPC		0.29
ClinPred		0.023	T
GERP RS		4.1
Varity_R		0.34
gMVP		0.45
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs115597604; hg19: chr17-8224279;