rs1354034

chr3-56815721-T-C

Variant summary

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

The ENST00000338458.8(ARHGEF3):c.193-41905A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.495 in 152,046 control chromosomes in the GnomAD database, including 20,681 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 0.49 (20681 hom., cov: 32)
• Consequence: ARHGEF3 ENST00000338458.8 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.81

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=-0.6).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.604 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARHGEF3	NM_001128615.2	c.193-41905A>G		intron_variant
ARHGEF3	NM_001289698.2	c.115-41905A>G		intron_variant
ARHGEF3	NM_001377407.1	c.193-41905A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARHGEF3	ENST00000338458.8	c.193-41905A>G		intron_variant		1
ARHGEF3	ENST00000468466.1	c.193-41905A>G		intron_variant		4
ARHGEF3	ENST00000468727.5	c.100-41905A>G		intron_variant		3

Frequencies

GnomAD3 genomes AF: 0.495 AC: 75213 AN: 151928 Hom.: 20681 Cov.: 32

Gnomad AFR AF: 0.253

Gnomad AMI AF: 0.526

Gnomad AMR AF: 0.454

Gnomad ASJ AF: 0.533

Gnomad EAS AF: 0.573

Gnomad SAS AF: 0.517

Gnomad FIN AF: 0.711

Gnomad MID AF: 0.475

Gnomad NFE AF: 0.609

Gnomad OTH AF: 0.485

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

GnomAD4 genome AF: 0.495 AC: 75236 AN: 152046 Hom.: 20681 Cov.: 32 AF XY: 0.498 AC XY: 36999 AN XY: 74318

Gnomad4 AFR AF: 0.253

Gnomad4 AMR AF: 0.453

Gnomad4 ASJ AF: 0.533

Gnomad4 EAS AF: 0.573

Gnomad4 SAS AF: 0.518

Gnomad4 FIN AF: 0.711

Gnomad4 NFE AF: 0.609

Gnomad4 OTH AF: 0.483

Alfa AF: 0.577 Hom.: 56259

Bravo AF: 0.463

Asia WGS AF: 0.496 AC: 1725 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
Cadd	Benign	13
Dann	Benign	0.75

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1354034; hg19: chr3-56849749;