Variant rs3772219 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

The ENST00000296315.8(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
ENST00000296315.8 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.990

Variant links:

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]

ARHGEF3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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	Protein	UniProt
ARHGEF3	NM_019555.3 linkuse as main transcript	c.1003T>G	p.Leu335Val	missense_variant	8/10	ENST00000296315.8	NP_062455.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARHGEF3	ENST00000296315.8 linkuse as main transcript	c.1003T>G	p.Leu335Val	missense_variant	8/10	1	NM_019555.3	ENSP00000296315	P1	Q9NR81-1

Frequencies

GnomAD3 genomes

AF:

0.381

AC:

57929

AN:

151886

Hom.:

11893

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.322

AC XY:

234226

AN XY:

726956

show subpopulations

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.:

AF XY:

0.379

AC XY:

28185

AN XY:

74304

show subpopulations

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

BayesDel_noAF

Benign

-0.47

CADD

Benign

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

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

MutationAssessor

Uncertain

2.5

M;.;.;.;.;.

MutationTaster

Benign

0.00011

P;P;P;P;P;P

PrimateAI

Benign

0.48

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over