rs1500711

Positions:

• chr3-56880126-T-C

Variant summary

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

The ENST00000338458.8(ARHGEF3):​c.192+2166A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.343 in 152,038 control chromosomes in the GnomAD database, including 10,533 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 0.34 (10533 hom., cov: 32)
• Consequence: ARHGEF3 ENST00000338458.8 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.284

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=-0.72).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.491 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARHGEF3	NM_001128615.2	c.192+2166A>G		intron_variant			NP_001122087.1
ARHGEF3	NM_001289698.2	c.114+2166A>G		intron_variant			NP_001276627.1
ARHGEF3	NM_001377407.1	c.192+2166A>G		intron_variant			NP_001364336.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARHGEF3	ENST00000338458.8	c.192+2166A>G		intron_variant		1		ENSP00000341071
ARHGEF3	ENST00000468466.1	c.192+2166A>G		intron_variant		4		ENSP00000418469
ARHGEF3	ENST00000468727.5	c.99+2166A>G		intron_variant		3		ENSP00000417087

Frequencies

GnomAD3 genomes AF: 0.343 AC: 52103 AN: 151920 Hom.: 10528 Cov.: 32

Gnomad AFR AF: 0.118

Gnomad AMI AF: 0.479

Gnomad AMR AF: 0.388

Gnomad ASJ AF: 0.445

Gnomad EAS AF: 0.508

Gnomad SAS AF: 0.359

Gnomad FIN AF: 0.438

Gnomad MID AF: 0.411

Gnomad NFE AF: 0.433

Gnomad OTH AF: 0.385

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

GnomAD4 genome AF: 0.343 AC: 52114 AN: 152038 Hom.: 10533 Cov.: 32 AF XY: 0.345 AC XY: 25601 AN XY: 74298

Gnomad4 AFR AF: 0.117

Gnomad4 AMR AF: 0.389

Gnomad4 ASJ AF: 0.445

Gnomad4 EAS AF: 0.507

Gnomad4 SAS AF: 0.360

Gnomad4 FIN AF: 0.438

Gnomad4 NFE AF: 0.433

Gnomad4 OTH AF: 0.383

Alfa AF: 0.421 Hom.: 18411

Bravo AF: 0.332

Asia WGS AF: 0.419 AC: 1453 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	13
DANN	Benign	0.86

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1500711; hg19: chr3-56914154;