rs200402507

Variant names:

• chr17-8319526-C-T
• rs200402507
• NM_173728.4:c.2297C>T

Your query was ambiguous. Multiple possible variants found:

• chr17-8319526-C-T
• chr17-8319526-C-G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_173728.4(ARHGEF15):​c.2297C>T​(p.Ser766Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000646 in 1,610,512 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 (★★). Synonymous variant affecting the same amino acid position (i.e. S766S) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.000085 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000062 (0 hom.)
• Consequence: ARHGEF15 NM_173728.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.96
• 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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.08037543).
• BS2: High AC in GnomAd4 at 13 AD,Unknown 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGEF15	NM_173728.4	MANE Select	c.2297C>T	p.Ser766Leu	missense	Exon 15 of 16	NP_776089.2
	ARHGEF15	NM_025014.2		c.2297C>T	p.Ser766Leu	missense	Exon 15 of 16	NP_079290.1	O94989

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGEF15	ENST00000361926.8	TSL:1 MANE Select	c.2297C>T	p.Ser766Leu	missense	Exon 15 of 16	ENSP00000355026.3	O94989
	ARHGEF15	ENST00000421050.2	TSL:1	c.2297C>T	p.Ser766Leu	missense	Exon 15 of 16	ENSP00000412505.1	O94989
	ARHGEF15	ENST00000852584.1		c.2342C>T	p.Ser781Leu	missense	Exon 15 of 16	ENSP00000522643.1

Frequencies

GnomAD3 genomes AF: 0.0000854 AC: 13 AN: 152234 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000323 AC: 8 AN: 247672 AF XY: 0.0000448

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000297

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000549

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000445

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000624 AC: 91 AN: 1458160 Hom.: 0 Cov.: 31 AF XY: 0.0000565 AC XY: 41 AN XY: 725320

African (AFR) AF: 0.0000301 AC: 1 AN: 33254

American (AMR) AF: 0.0000456 AC: 2 AN: 43860

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25860

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39658

South Asian (SAS) AF: 0.0000234 AC: 2 AN: 85650

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53326

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5740

European-Non Finnish (NFE) AF: 0.0000702 AC: 78 AN: 1110622

Other (OTH) AF: 0.0000831 AC: 5 AN: 60190

GnomAD4 genome AF: 0.0000853 AC: 13 AN: 152352 Hom.: 0 Cov.: 32 AF XY: 0.0000537 AC XY: 4 AN XY: 74512

African (AFR) AF: 0.0000481 AC: 2 AN: 41586

American (AMR) AF: 0.00 AC: 0 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.0000416

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.40	T
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.30
FATHMM_MKL	Benign	0.56	D
LIST_S2	Benign	0.60	T
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.080	T
MetaSVM	Benign	-0.73	T
PhyloP100		2.0
PrimateAI	Benign	0.31	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.12
Sift	Uncertain	0.012	D
Sift4G	Benign	0.17	T
Polyphen		0.036	B
Vest4		0.23
MVP		0.71
MPC		0.14
ClinPred		0.093	T
GERP RS		4.5
Varity_R		0.063
gMVP		0.26
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs200402507; hg19: chr17-8222844; COSMIC: COSV62725761; COSMIC: COSV62725761;