17-8312106-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_173728.4(ARHGEF15):c.67C>T(p.Arg23Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00337 in 1,581,580 control chromosomes in the GnomAD database, including 310 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R23H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0078 (47 hom., cov: 22)
  • Exomes 𝑓: 0.0029 (263 hom.)
• Consequence: ARHGEF15 NM_173728.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.36

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0028896034).
• BP6: Variant 17-8312106-C-T is Benign according to our data. Variant chr17-8312106-C-T is described in ClinVar as [Benign]. Clinvar id is 242022.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0665 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARHGEF15	NM_173728.4	c.67C>T	p.Arg23Cys	missense_variant	2/16	ENST00000361926.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARHGEF15	ENST00000361926.8	c.67C>T	p.Arg23Cys	missense_variant	2/16	1	NM_173728.4	P1

Frequencies

GnomAD3 genomes AF: 0.00778 AC: 1161 AN: 149206 Hom.: 48 Cov.: 22

Gnomad AFR AF: 0.00192

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0701

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: 0.000193

Gnomad OTH AF: 0.0122

GnomAD3 exomes AF: 0.0134 AC: 3042 AN: 227000 Hom.: 202 AF XY: 0.00985 AC XY: 1208 AN XY: 122650

Gnomad AFR exome AF: 0.00198

Gnomad AMR exome AF: 0.0971

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000593

Gnomad SAS exome AF: 0.0000736

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000681

Gnomad OTH exome AF: 0.0105

GnomAD4 exome AF: 0.00291 AC: 4161 AN: 1432260 Hom.: 263 Cov.: 36 AF XY: 0.00245 AC XY: 1747 AN XY: 711924

Gnomad4 AFR exome AF: 0.00138

Gnomad4 AMR exome AF: 0.0978

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000520

Gnomad4 SAS exome AF: 0.0000606

Gnomad4 FIN exome AF: 0.0000190

Gnomad4 NFE exome AF: 0.0000355

Gnomad4 OTH exome AF: 0.00298

GnomAD4 genome AF: 0.00778 AC: 1162 AN: 149320 Hom.: 47 Cov.: 22 AF XY: 0.00908 AC XY: 661 AN XY: 72812

Gnomad4 AFR AF: 0.00191

Gnomad4 AMR AF: 0.0701

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000193

Gnomad4 OTH AF: 0.0121

Alfa AF: 0.00216 Hom.: 5

Bravo AF: 0.0132

ESP6500AA AF: 0.00250 AC: 11

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00943 AC: 1145

Asia WGS AF: 0.00520 AC: 18 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Early infantile epileptic encephalopathy with suppression bursts Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

ARHGEF15-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 13, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.21
Cadd	Pathogenic	26
Dann	Uncertain	0.99
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.88	D;.;D;D
MetaRNN	Benign	0.0029	T;T;T;T
MetaSVM	Benign	-0.74	T
MutationTaster	Benign	0.94	D;D
PrimateAI	Uncertain	0.58	T
Sift4G	Uncertain	0.051	T;D;T;D
Polyphen		1.0	.;D;.;D
Vest4		0.51, 0.52
MPC		0.53
ClinPred		0.028	T
GERP RS		5.0
Varity_R		0.24
gMVP		0.29

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

Publications

LitVar

Other links and lift over

dbSNP: rs137909519; hg19: chr17-8215424;