rs79993581

chr17-8319552-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_173728.4(ARHGEF15):c.2323C>T(p.Arg775Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0263 in 1,611,294 control chromosomes in the GnomAD database, including 694 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict 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. R775Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.022 (49 hom., cov: 32)
  • Exomes 𝑓: 0.027 (645 hom.)
• Consequence: ARHGEF15 NM_173728.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.92

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0026908517).
• BP6: Variant 17-8319552-C-T is Benign according to our data. Variant chr17-8319552-C-T is described in ClinVar as [Benign]. Clinvar id is 242019.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-8319552-C-T is described in Lovd as [Benign].
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0556 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARHGEF15	NM_173728.4	c.2323C>T	p.Arg775Trp	missense_variant	15/16	ENST00000361926.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARHGEF15	ENST00000361926.8	c.2323C>T	p.Arg775Trp	missense_variant	15/16	1	NM_173728.4	P1
ARHGEF15	ENST00000421050.2	c.2323C>T	p.Arg775Trp	missense_variant	15/16	1		P1
ARHGEF15	ENST00000647883.1	c.1786C>T	p.Arg596Trp	missense_variant	12/13

Frequencies

GnomAD3 genomes AF: 0.0224 AC: 3402 AN: 152196 Hom.: 49 Cov.: 32

Gnomad AFR AF: 0.0201

Gnomad AMI AF: 0.0658

Gnomad AMR AF: 0.0177

Gnomad ASJ AF: 0.0236

Gnomad EAS AF: 0.000769

Gnomad SAS AF: 0.0379

Gnomad FIN AF: 0.00603

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.0267

Gnomad OTH AF: 0.0306

GnomAD3 exomes AF: 0.0234 AC: 5816 AN: 248436 Hom.: 108 AF XY: 0.0255 AC XY: 3430 AN XY: 134286

Gnomad AFR exome AF: 0.0192

Gnomad AMR exome AF: 0.0150

Gnomad ASJ exome AF: 0.0266

Gnomad EAS exome AF: 0.0000549

Gnomad SAS exome AF: 0.0406

Gnomad FIN exome AF: 0.00802

Gnomad NFE exome AF: 0.0282

Gnomad OTH exome AF: 0.0268

GnomAD4 exome AF: 0.0267 AC: 39010 AN: 1458980 Hom.: 645 Cov.: 32 AF XY: 0.0275 AC XY: 19990 AN XY: 725794

Gnomad4 AFR exome AF: 0.0221

Gnomad4 AMR exome AF: 0.0165

Gnomad4 ASJ exome AF: 0.0289

Gnomad4 EAS exome AF: 0.0000757

Gnomad4 SAS exome AF: 0.0416

Gnomad4 FIN exome AF: 0.00961

Gnomad4 NFE exome AF: 0.0276

Gnomad4 OTH exome AF: 0.0280

GnomAD4 genome AF: 0.0223 AC: 3403 AN: 152314 Hom.: 49 Cov.: 32 AF XY: 0.0215 AC XY: 1605 AN XY: 74484

Gnomad4 AFR AF: 0.0200

Gnomad4 AMR AF: 0.0177

Gnomad4 ASJ AF: 0.0236

Gnomad4 EAS AF: 0.000771

Gnomad4 SAS AF: 0.0382

Gnomad4 FIN AF: 0.00603

Gnomad4 NFE AF: 0.0268

Gnomad4 OTH AF: 0.0307

Alfa AF: 0.0252 Hom.: 72

Bravo AF: 0.0234

TwinsUK AF: 0.0245 AC: 91

ALSPAC AF: 0.0280 AC: 108

ESP6500AA AF: 0.0191 AC: 84

ESP6500EA AF: 0.0253 AC: 218

ExAC AF: 0.0247 AC: 2997

Asia WGS AF: 0.0200 AC: 69 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Early infantile epileptic encephalopathy with suppression bursts Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.38
Cadd	Benign	21
Dann	Uncertain	1.0
DEOGEN2	Benign	0.21	T;T;.
Eigen	Benign	-0.055
Eigen_PC	Benign	-0.0059
FATHMM_MKL	Uncertain	0.76	D
MetaRNN	Benign	0.0027	T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.98	N;N
PrimateAI	Benign	0.20	T
PROVEAN	Benign	-0.22	N;N;.
REVEL	Benign	0.13
Sift	Uncertain	0.020	D;D;.
Sift4G	Uncertain	0.017	D;D;.
Polyphen		0.99	D;D;.
Vest4		0.15
MPC		0.17
ClinPred		0.015	T
GERP RS		4.5
Varity_R		0.044
gMVP		0.53

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs79993581; hg19: chr17-8222870;