NM_173728.4:c.2101C>T

Variant names:

• chr17-8319074-C-T
• rs1555547506
• NM_173728.4:c.2101C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_173728.4(ARHGEF15):​c.2101C>T​(p.Pro701Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ARHGEF15 NM_173728.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.49
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14594564).

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.2101C>T	p.Pro701Ser	missense	Exon 13 of 16	NP_776089.2
	ARHGEF15	NM_025014.2		c.2101C>T	p.Pro701Ser	missense	Exon 13 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.2101C>T	p.Pro701Ser	missense	Exon 13 of 16	ENSP00000355026.3
	ARHGEF15	ENST00000421050.2	TSL:1	c.2101C>T	p.Pro701Ser	missense	Exon 13 of 16	ENSP00000412505.1
	ARHGEF15	ENST00000647883.1		c.1564C>T	p.Pro522Ser	missense	Exon 10 of 13	ENSP00000498197.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Developmental and epileptic encephalopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.0043	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.035	T
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.066
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.040	D
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-0.32	T
PhyloP100		1.5
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	1.0	N
REVEL	Benign	0.23
Sift	Benign	0.14	T
Sift4G	Benign	0.93	T
Polyphen		0.15	B
Vest4		0.31
MutPred		0.20		Gain of phosphorylation at P701 (P = 0.069)
MVP		0.84
MPC		0.23
ClinPred		0.69	D
GERP RS		5.0
Varity_R		0.062
gMVP		0.29

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs1555547506; hg19: chr17-8222392;