rs3772219

chr3-56737223-A-Cchr3-56737223-A-Gchr3-56737223-A-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_019555.3(ARHGEF3):c.1003T>G(p.Leu335Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.332 in 1,613,268 control chromosomes in the GnomAD database, including 92,669 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.38 (11921 hom., cov: 32)
  • Exomes 𝑓: 0.33 (80748 hom.)
• Consequence: ARHGEF3 NM_019555.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.990

Genes affected

ARHGEF3 (HGNC:683): (Rho guanine nucleotide exchange factor 3) Rho-like GTPases are involved in a variety of cellular processes, and they are activated by binding GTP and inactivated by conversion of GTP to GDP by their intrinsic GTPase activity. Guanine nucleotide exchange factors (GEFs) accelerate the GTPase activity of Rho GTPases by catalyzing their release of bound GDP. This gene encodes a guanine nucleotide exchange factor, which specifically activates two members of the Rho GTPase family: RHOA and RHOB, both of which have a role in bone cell biology. It has been identified that genetic variation in this gene plays a role in the determination of bone mineral density (BMD), indicating the implication of this gene in postmenopausal osteoporosis. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.9623508E-4).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.516 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARHGEF3	NM_019555.3	c.1003T>G	p.Leu335Val	missense_variant	8/10	ENST00000296315.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARHGEF3	ENST00000296315.8	c.1003T>G	p.Leu335Val	missense_variant	8/10	1	NM_019555.3	P1

Frequencies

GnomAD3 genomes AF: 0.381 AC: 57929 AN: 151886 Hom.: 11893 Cov.: 32

Gnomad AFR AF: 0.522

Gnomad AMI AF: 0.367

Gnomad AMR AF: 0.454

Gnomad ASJ AF: 0.217

Gnomad EAS AF: 0.445

Gnomad SAS AF: 0.277

Gnomad FIN AF: 0.290

Gnomad MID AF: 0.174

Gnomad NFE AF: 0.306

Gnomad OTH AF: 0.357

GnomAD3 exomes AF: 0.349 AC: 87743 AN: 251358 Hom.: 16712 AF XY: 0.334 AC XY: 45444 AN XY: 135862

Gnomad AFR exome AF: 0.525

Gnomad AMR exome AF: 0.520

Gnomad ASJ exome AF: 0.227

Gnomad EAS exome AF: 0.437

Gnomad SAS exome AF: 0.278

Gnomad FIN exome AF: 0.288

Gnomad NFE exome AF: 0.302

Gnomad OTH exome AF: 0.309

GnomAD4 exome AF: 0.327 AC: 477624 AN: 1461264 Hom.: 80748 Cov.: 36 AF XY: 0.322 AC XY: 234226 AN XY: 726956

Gnomad4 AFR exome AF: 0.516

Gnomad4 AMR exome AF: 0.513

Gnomad4 ASJ exome AF: 0.230

Gnomad4 EAS exome AF: 0.412

Gnomad4 SAS exome AF: 0.280

Gnomad4 FIN exome AF: 0.285

Gnomad4 NFE exome AF: 0.319

Gnomad4 OTH exome AF: 0.338

GnomAD4 genome AF: 0.382 AC: 58017 AN: 152004 Hom.: 11921 Cov.: 32 AF XY: 0.379 AC XY: 28185 AN XY: 74304

Gnomad4 AFR AF: 0.522

Gnomad4 AMR AF: 0.455

Gnomad4 ASJ AF: 0.217

Gnomad4 EAS AF: 0.446

Gnomad4 SAS AF: 0.278

Gnomad4 FIN AF: 0.290

Gnomad4 NFE AF: 0.306

Gnomad4 OTH AF: 0.360

Alfa AF: 0.309 Hom.: 19388

Bravo AF: 0.401

TwinsUK AF: 0.330 AC: 1225

ALSPAC AF: 0.307 AC: 1185

ESP6500AA AF: 0.524 AC: 2309

ESP6500EA AF: 0.304 AC: 2611

ExAC AF: 0.341 AC: 41412

Asia WGS AF: 0.370 AC: 1287 AN: 3478

EpiCase AF: 0.287

EpiControl AF: 0.294

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.47
Cadd	Benign	17
Dann	Uncertain	1.0
DEOGEN2	Benign	0.28	T;.;.;T;T;T
Eigen	Benign	-0.098
Eigen_PC	Benign	-0.064
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.80	T;T;T;T;T;T
MetaRNN	Benign	0.00030	T;T;T;T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Uncertain	2.5	M;.;.;.;.;.
MutationTaster	Benign	0.00011	P;P;P;P;P;P
PrimateAI	Benign	0.48	T
PROVEAN	Uncertain	-2.8	D;D;D;D;D;D
REVEL	Benign	0.077
Sift	Benign	0.033	D;D;D;D;D;D
Sift4G	Uncertain	0.045	D;D;D;D;D;D
Polyphen		0.21	B;P;B;B;B;B
Vest4		0.099
MPC		0.80
ClinPred		0.046	T
GERP RS		0.52
Varity_R		0.23
gMVP		0.49

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: rs3772219; hg19: chr3-56771251; COSMIC: COSV56324674;