17-8312119-G-C

Variant names:

• chr17-8312119-G-C
• rs199663714
• NM_173728.4:c.80G>C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_173728.4(ARHGEF15):​c.80G>C​(p.Arg27Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000704 in 1,278,664 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R27H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 20)
  • Exomes 𝑓: 0.0000070 (0 hom.)
• Consequence: ARHGEF15 NM_173728.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.38
• Publications: 1 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: Likely_benign. The variant received -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 9 Unknown,AD gene.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGEF15	NM_173728.4	MANE Select	c.80G>C	p.Arg27Pro	missense	Exon 2 of 16	NP_776089.2
	ARHGEF15	NM_025014.2		c.80G>C	p.Arg27Pro	missense	Exon 2 of 16	NP_079290.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGEF15	ENST00000361926.8	TSL:1 MANE Select	c.80G>C	p.Arg27Pro	missense	Exon 2 of 16	ENSP00000355026.3
	ARHGEF15	ENST00000421050.2	TSL:1	c.80G>C	p.Arg27Pro	missense	Exon 2 of 16	ENSP00000412505.1
	ARHGEF15	ENST00000579439.5	TSL:5	c.80G>C	p.Arg27Pro	missense	Exon 2 of 3	ENSP00000464540.1

Frequencies

GnomAD3 genomes Cov.: 20

GnomAD2 exomes AF: 0.00000549 AC: 1 AN: 182036 AF XY: 0.00000997

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000704 AC: 9 AN: 1278664 Hom.: 0 Cov.: 39 AF XY: 0.0000111 AC XY: 7 AN XY: 628156

African (AFR) AF: 0.00 AC: 0 AN: 27756

American (AMR) AF: 0.00 AC: 0 AN: 31294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20878

East Asian (EAS) AF: 0.00 AC: 0 AN: 31492

South Asian (SAS) AF: 0.000141 AC: 8 AN: 56636

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45946

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5026

European-Non Finnish (NFE) AF: 9.91e-7 AC: 1 AN: 1008640

Other (OTH) AF: 0.00 AC: 0 AN: 50996

GnomAD4 genome Cov.: 20

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 27, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.80G>C (p.R27P) alteration is located in exon 2 (coding exon 1) of the ARHGEF15 gene. This alteration results from a G to C substitution at nucleotide position 80, causing the arginine (R) at amino acid position 27 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.038	T
BayesDel_noAF	Benign	-0.16
CADD	Uncertain	26
DANN	Benign	0.91
DEOGEN2	Benign	0.064	T
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.76	T
M_CAP	Uncertain	0.18	D
MetaRNN	Uncertain	0.49	T
MetaSVM	Benign	-0.40	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		3.4
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	0.090	N
REVEL	Benign	0.29
Sift	Uncertain	0.0010	D
Sift4G	Benign	0.18	T
Polyphen		1.0	D
Vest4		0.42
MutPred		0.41		Gain of glycosylation at R27 (P = 0.005)
MVP		0.88
MPC		0.54
ClinPred		0.88	D
GERP RS		5.0
Varity_R		0.18
gMVP		0.40
Mutation Taster		=86/14	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: rs199663714; hg19: chr17-8215437;