3-56892138-A-G

Variant names:

• chr3-56892138-A-G
• rs4681928
• ENST00000338458.8:c.130-9784T>C

Variant summary

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

The ENST00000338458.8(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 ENST00000338458.8 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.17
• Publications: 2 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=-0.84).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.701 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000338458.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGEF3	NM_001128615.2		c.130-9784T>C		intron	N/A	NP_001122087.1
	ARHGEF3	NM_001377407.1		c.130-9784T>C		intron	N/A	NP_001364336.1
	ARHGEF3	NM_001377408.1		c.70-9784T>C		intron	N/A	NP_001364337.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGEF3	ENST00000338458.8	TSL:1	c.130-9784T>C		intron	N/A	ENSP00000341071.4
	ARHGEF3	ENST00000496106.5	TSL:2	c.52-9784T>C		intron	N/A	ENSP00000420420.1
	ARHGEF3	ENST00000473779.5	TSL:3	c.88-9784T>C		intron	N/A	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

African (AFR) AF: 0.370 AC: 15316 AN: 41450

American (AMR) AF: 0.403 AC: 6150 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.366 AC: 1270 AN: 3470

East Asian (EAS) AF: 0.720 AC: 3719 AN: 5162

South Asian (SAS) AF: 0.358 AC: 1722 AN: 4814

European-Finnish (FIN) AF: 0.215 AC: 2273 AN: 10570

Middle Eastern (MID) AF: 0.272 AC: 80 AN: 294

European-Non Finnish (NFE) AF: 0.223 AC: 15128 AN: 67958

Other (OTH) AF: 0.322 AC: 681 AN: 2112

Alfa AF: 0.260 Hom.: 22131

Bravo AF: 0.327

Asia WGS AF: 0.517 AC: 1794 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	8.0
DANN	Benign	0.76
PhyloP100		1.2
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: rs4681928; hg19: chr3-56926166;