rs6445834

Variant names:

• chr3-56881691-T-C
• rs6445834
• ENST00000338458.8:c.192+601A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000338458.8(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 ENST00000338458.8 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.642
• Publications: 4 publications found

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

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGEF3	NM_001128615.2	c.192+601A>G		intron_variant	Intron 4 of 12		NP_001122087.1
ARHGEF3	NM_001377407.1	c.192+601A>G		intron_variant	Intron 4 of 12		NP_001364336.1
ARHGEF3	NM_001377408.1	c.132+601A>G		intron_variant	Intron 6 of 14		NP_001364337.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARHGEF3	ENST00000338458.8	c.192+601A>G		intron_variant	Intron 4 of 12	1		ENSP00000341071.4
ARHGEF3	ENST00000496106.5	c.114+601A>G		intron_variant	Intron 2 of 10	2		ENSP00000420420.1
ARHGEF3	ENST00000473779.5	c.150+601A>G		intron_variant	Intron 3 of 6	3		ENSP00000420402.1

Frequencies

GnomAD3 genomes AF: 0.631 AC: 95867 AN: 151972 Hom.: 30608 Cov.: 32

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.: 32 AF XY: 0.626 AC XY: 46509 AN XY: 74334

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

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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.44
DANN	Benign	0.68
PhyloP100		-0.64
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs6445834; hg19: chr3-56915719;