rs4681928

Positions:

• chr3-56892138-A-G

Variant summary

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

The NM_001128615.2(ARHGEF3):​c.130-9784T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.306 in 152,016 control chromosomes in the GnomAD database, including 8,115 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 0.31 (8115 hom., cov: 32)
• Consequence: ARHGEF3 NM_001128615.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.17

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 (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.701 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARHGEF3	NM_001128615.2	c.130-9784T>C		intron_variant			NP_001122087.1
ARHGEF3	NM_001377407.1	c.130-9784T>C		intron_variant			NP_001364336.1
ARHGEF3	NM_001377408.1	c.70-9784T>C		intron_variant			NP_001364337.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARHGEF3	ENST00000338458.8	c.130-9784T>C		intron_variant		1		ENSP00000341071.4
ARHGEF3	ENST00000496106.5	c.52-9784T>C		intron_variant		2		ENSP00000420420.1
ARHGEF3	ENST00000473779.5	c.88-9784T>C		intron_variant		3		ENSP00000420402.1

Frequencies

GnomAD3 genomes AF: 0.306 AC: 46436 AN: 151898 Hom.: 8097 Cov.: 32

Gnomad AFR AF: 0.370

Gnomad AMI AF: 0.166

Gnomad AMR AF: 0.401

Gnomad ASJ AF: 0.366

Gnomad EAS AF: 0.721

Gnomad SAS AF: 0.358

Gnomad FIN AF: 0.215

Gnomad MID AF: 0.269

Gnomad NFE AF: 0.223

Gnomad OTH AF: 0.324

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

GnomAD4 genome AF: 0.306 AC: 46490 AN: 152016 Hom.: 8115 Cov.: 32 AF XY: 0.312 AC XY: 23170 AN XY: 74336

Gnomad4 AFR AF: 0.370

Gnomad4 AMR AF: 0.403

Gnomad4 ASJ AF: 0.366

Gnomad4 EAS AF: 0.720

Gnomad4 SAS AF: 0.358

Gnomad4 FIN AF: 0.215

Gnomad4 NFE AF: 0.223

Gnomad4 OTH AF: 0.322

Alfa AF: 0.253 Hom.: 8853

Bravo AF: 0.327

Asia WGS AF: 0.517 AC: 1794 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	8.0
DANN	Benign	0.76

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs4681928; hg19: chr3-56926166;