dbSNP rs6445834: ARHGEF3:c.192+601A>G (chr3-56881691-T-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_001128615.2(ARHGEF3):c.192+601A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.631 in 152,090 control chromosomes in the GnomAD database, including 30,616 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.

Frequency

Genomes: 𝑓 0.63 ( 30616 hom., cov: 32)

Consequence

ARHGEF3
NM_001128615.2 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.642

Publications

4 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 (BayesDel_noAF=-0.86).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.645 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001128615.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	HGVSc	Effect	Exon Rank	Protein	UniProt
ARHGEF3	NM_001128615.2	c.192+601A>G	intron	N/A	NP_001122087.1	Q9NR81-2
ARHGEF3	NM_001377407.1	c.192+601A>G	intron	N/A	NP_001364336.1	Q9NR81-2
ARHGEF3	NM_001377408.1	c.132+601A>G	intron	N/A	NP_001364337.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ARHGEF3	ENST00000338458.8	TSL:1	c.192+601A>G	intron	N/A	ENSP00000341071.4	Q9NR81-2
ARHGEF3	ENST00000496106.5	TSL:2	c.114+601A>G	intron	N/A	ENSP00000420420.1	E9PG37
ARHGEF3	ENST00000473779.5	TSL:3	c.150+601A>G	intron	N/A	ENSP00000420402.1	C9JNF2

Frequencies

GnomAD3 genomes

AF:

0.631

AC:

95867

AN:

151972

Hom.:

30608

Cov.:

show subpopulations

Gnomad AFR

AF:

0.652

Gnomad AMI

AF:

0.741

Gnomad AMR

AF:

0.621

Gnomad ASJ

AF:

0.560

Gnomad EAS

AF:

0.378

Gnomad SAS

AF:

0.493

Gnomad FIN

AF:

0.655

Gnomad MID

AF:

0.615

Gnomad NFE

AF:

0.648

Gnomad OTH

AF:

0.606

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.631

AC:

95912

AN:

152090

Hom.:

30616

Cov.:

AF XY:

0.626

AC XY:

46509

AN XY:

74334

show subpopulations

African (AFR)

AF:

0.652

AC:

27045

AN:

41506

American (AMR)

AF:

0.620

AC:

9475

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.560

AC:

1944

AN:

3472

East Asian (EAS)

AF:

0.378

AC:

1959

AN:

5178

South Asian (SAS)

AF:

0.491

AC:

2368

AN:

4818

European-Finnish (FIN)

AF:

0.655

AC:

6912

AN:

10548

Middle Eastern (MID)

AF:

0.603

AC:

176

AN:

292

European-Non Finnish (NFE)

AF:

0.648

AC:

44080

AN:

67974

Other (OTH)

AF:

0.605

AC:

1277

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

1821

3642

5464

7285

9106

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

784

1568

2352

3136

3920

<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:

0.637

Hom.:

62262

Bravo

AF:

0.630

Asia WGS

AF:

0.428

AC:

1494

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

0.44

(source)

DANN

Benign

0.68

PhyloP100

-0.64

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over