rs1354034

Variant names:

• chr3-56815721-T-C
• rs1354034
• ENST00000338458.8:c.193-41905A>G

Variant summary

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

The NM_001128615.2(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 NM_001128615.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.81
• Publications: 70 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=-0.6).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.604 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGEF3	NM_001128615.2		c.193-41905A>G		intron	N/A	NP_001122087.1
	ARHGEF3	NM_001377407.1		c.193-41905A>G		intron	N/A	NP_001364336.1
	ARHGEF3	NM_001377408.1		c.133-41905A>G		intron	N/A	NP_001364337.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGEF3	ENST00000338458.8	TSL:1	c.193-41905A>G		intron	N/A	ENSP00000341071.4
	ARHGEF3	ENST00000496106.5	TSL:2	c.115-41905A>G		intron	N/A	ENSP00000420420.1
	ARHGEF3	ENST00000473779.5	TSL:3	c.151-41905A>G		intron	N/A	ENSP00000420402.1

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

African (AFR) AF: 0.253 AC: 10501 AN: 41490

American (AMR) AF: 0.453 AC: 6925 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.533 AC: 1846 AN: 3466

East Asian (EAS) AF: 0.573 AC: 2962 AN: 5168

South Asian (SAS) AF: 0.518 AC: 2497 AN: 4818

European-Finnish (FIN) AF: 0.711 AC: 7515 AN: 10566

Middle Eastern (MID) AF: 0.466 AC: 137 AN: 294

European-Non Finnish (NFE) AF: 0.609 AC: 41354 AN: 67940

Other (OTH) AF: 0.483 AC: 1019 AN: 2110

Alfa AF: 0.565 Hom.: 116080

Bravo AF: 0.463

Asia WGS AF: 0.496 AC: 1725 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	13
DANN	Benign	0.75
PhyloP100		1.8
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: rs1354034; hg19: chr3-56849749;