NM_173728.4:c.618C>G

Variant names:

• chr17-8312938-C-G
• rs138521691
• NM_173728.4:c.618C>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.309
• Publications: 0 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: 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).

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.618C>G	p.Cys206Trp	missense	Exon 3 of 16	NP_776089.2
	ARHGEF15	NM_025014.2		c.618C>G	p.Cys206Trp	missense	Exon 3 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.618C>G	p.Cys206Trp	missense	Exon 3 of 16	ENSP00000355026.3
	ARHGEF15	ENST00000421050.2	TSL:1	c.618C>G	p.Cys206Trp	missense	Exon 3 of 16	ENSP00000412505.1
	ARHGEF15	ENST00000579439.5	TSL:5	c.618C>G	p.Cys206Trp	missense	Exon 3 of 3	ENSP00000464540.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 7.01e-7 AC: 1 AN: 1426982 Hom.: 0 Cov.: 33 AF XY: 0.00000142 AC XY: 1 AN XY: 705748

African (AFR) AF: 0.00 AC: 0 AN: 33002

American (AMR) AF: 0.00 AC: 0 AN: 42504

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23416

East Asian (EAS) AF: 0.00 AC: 0 AN: 39468

South Asian (SAS) AF: 0.00 AC: 0 AN: 79734

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49466

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5592

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1094810

Other (OTH) AF: 0.0000170 AC: 1 AN: 58990

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Benign	-0.061	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	19
DANN	Benign	0.90
DEOGEN2	Benign	0.055	T
Eigen	Benign	-0.019
Eigen_PC	Benign	-0.073
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.37	T
M_CAP	Benign	0.065	D
MetaRNN	Benign	0.35	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.1	L
PhyloP100		-0.31
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.080	N
REVEL	Benign	0.21
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.019	D
Polyphen		1.0	D
Vest4		0.64
MutPred		0.31		Loss of disorder (P = 0.0271)
MVP		0.81
MPC		0.53
ClinPred		0.89	D
GERP RS		2.3
PromoterAI		0.021	Neutral
Varity_R		0.63
gMVP		0.60
Mutation Taster		=95/5	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: rs138521691; hg19: chr17-8216256;