rs76729434

Variant names:

• chr17-8319595-C-A
• rs76729434
• NM_173728.4:c.2366C>A

Your query was ambiguous. Multiple possible variants found:

• chr17-8319595-C-A
• chr17-8319595-C-T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_025014.2(ARHGEF15):​c.2366C>A​(p.Thr789Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000766 in 1,567,452 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0043 (6 hom., cov: 32)
  • Exomes 𝑓: 0.00038 (5 hom.)
• Consequence: ARHGEF15 NM_025014.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.668
• 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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005372435).
• BP6: Variant 17-8319595-C-A is Benign according to our data. Variant chr17-8319595-C-A is described in ClinVar as Benign. ClinVar VariationId is 412679.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 662 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.2366C>A	p.Thr789Asn	missense	Exon 15 of 16	NP_776089.2
	ARHGEF15	NM_025014.2		c.2366C>A	p.Thr789Asn	missense	Exon 15 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.2366C>A	p.Thr789Asn	missense	Exon 15 of 16	ENSP00000355026.3
	ARHGEF15	ENST00000421050.2	TSL:1	c.2366C>A	p.Thr789Asn	missense	Exon 15 of 16	ENSP00000412505.1
	ARHGEF15	ENST00000852584.1		c.2411C>A	p.Thr804Asn	missense	Exon 15 of 16	ENSP00000522643.1

Frequencies

GnomAD3 genomes AF: 0.00435 AC: 662 AN: 152146 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.0151

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00184

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: 0.0000588

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00116 AC: 245 AN: 210850 AF XY: 0.000810

Gnomad AFR exome AF: 0.0145

Gnomad AMR exome AF: 0.000665

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000196

Gnomad OTH exome AF: 0.000415

GnomAD4 exome AF: 0.000381 AC: 539 AN: 1415188 Hom.: 5 Cov.: 31 AF XY: 0.000326 AC XY: 229 AN XY: 703476

African (AFR) AF: 0.0143 AC: 440 AN: 30828

American (AMR) AF: 0.000862 AC: 27 AN: 31338

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23488

East Asian (EAS) AF: 0.00 AC: 0 AN: 38778

South Asian (SAS) AF: 0.0000129 AC: 1 AN: 77634

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51880

Middle Eastern (MID) AF: 0.000547 AC: 3 AN: 5484

European-Non Finnish (NFE) AF: 0.0000118 AC: 13 AN: 1097620

Other (OTH) AF: 0.000946 AC: 55 AN: 58138

GnomAD4 genome AF: 0.00435 AC: 662 AN: 152264 Hom.: 6 Cov.: 32 AF XY: 0.00419 AC XY: 312 AN XY: 74446

African (AFR) AF: 0.0150 AC: 625 AN: 41566

American (AMR) AF: 0.00183 AC: 28 AN: 15264

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

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

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68028

Other (OTH) AF: 0.00237 AC: 5 AN: 2112

Alfa AF: 0.00170 Hom.: 4

Bravo AF: 0.00454

ESP6500AA AF: 0.0143 AC: 63

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00128 AC: 155

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	ARHGEF15-related disorder (1)
-	-	1	Developmental and epileptic encephalopathy (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	10
DANN	Benign	0.89
DEOGEN2	Benign	0.18	T
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.46
FATHMM_MKL	Benign	0.40	N
LIST_S2	Benign	0.55	T
MetaRNN	Benign	0.0054	T
MetaSVM	Benign	-0.90	T
PhyloP100		0.67
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.10
Sift	Benign	0.44	T
Sift4G	Benign	0.22	T
Polyphen		0.0010	B
Vest4		0.20
MVP		0.73
MPC		0.19
ClinPred		0.011	T
GERP RS		-1.1
Varity_R		0.038
gMVP		0.30
Mutation Taster		=96/4	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: rs76729434; hg19: chr17-8222913;