Genetic Variant NM_019555.3:c.1003T>G (chr3-56737223-A-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

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. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.38 ( 11921 hom., cov: 32)

Exomes 𝑓: 0.33 ( 80748 hom. )

Consequence

ARHGEF3
NM_019555.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.990

Publications

44 publications found

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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
ARHGEF3	NM_019555.3 link	c.1003T>G	p.Leu335Val	missense_variant	Exon 8 of 10	ENST00000296315.8	NP_062455.1	Q9NR81-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARHGEF3	ENST00000296315.8 link	c.1003T>G	p.Leu335Val	missense_variant	Exon 8 of 10	1	NM_019555.3	ENSP00000296315.3		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

GnomAD2 exomes

AF:

0.349

AC:

87743

AN:

251358

AF XY:

0.334

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 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

African (AFR)

AF:

0.516

AC:

17286

AN:

33470

American (AMR)

AF:

0.513

AC:

22951

AN:

44702

Ashkenazi Jewish (ASJ)

AF:

0.230

AC:

6012

AN:

26126

East Asian (EAS)

AF:

0.412

AC:

16368

AN:

39694

South Asian (SAS)

AF:

0.280

AC:

24146

AN:

86226

European-Finnish (FIN)

AF:

0.285

AC:

15218

AN:

53410

Middle Eastern (MID)

AF:

0.192

AC:

1103

AN:

5738

European-Non Finnish (NFE)

AF:

0.319

AC:

354119

AN:

1111532

Other (OTH)

AF:

0.338

AC:

20421

AN:

60366

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

16756

33512

50268

67024

83780

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

11904

23808

35712

47616

59520

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.382

AC:

58017

AN:

152004

Hom.:

11921

Cov.:

AF XY:

0.379

AC XY:

28185

AN XY:

74304

show subpopulations

African (AFR)

AF:

0.522

AC:

21656

AN:

41470

American (AMR)

AF:

0.455

AC:

6939

AN:

15254

Ashkenazi Jewish (ASJ)

AF:

0.217

AC:

753

AN:

3470

East Asian (EAS)

AF:

0.446

AC:

2299

AN:

5160

South Asian (SAS)

AF:

0.278

AC:

1337

AN:

4812

European-Finnish (FIN)

AF:

0.290

AC:

3060

AN:

10558

Middle Eastern (MID)

AF:

0.187

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.306

AC:

20823

AN:

67964

Other (OTH)

AF:

0.360

AC:

761

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1737

3474

5212

6949

8686

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

534

1068

1602

2136

2670

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.326

Hom.:

34166

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

(source)

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;.;.;.;.;.

PhyloP100

0.99

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

Mutation Taster

=98/2

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over