3-56831748-A-G

Variant names:

• chr3-56831748-A-G
• rs12485738
• ENST00000338458.8:c.192+50544T>C

Variant summary

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

The ENST00000338458.8(ARHGEF3):​c.192+50544T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.626 in 152,110 control chromosomes in the GnomAD database, including 30,114 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 (30114 hom., cov: 33)
• Consequence: ARHGEF3 ENST00000338458.8 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.37
• Publications: 44 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 (AFR) allele frequency at 95% confidence interval = 0.649 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGEF3	NM_001128615.2	c.192+50544T>C		intron_variant	Intron 4 of 12		NP_001122087.1
ARHGEF3	NM_001377407.1	c.192+50544T>C		intron_variant	Intron 4 of 12		NP_001364336.1
ARHGEF3	NM_001377408.1	c.132+50544T>C		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+50544T>C		intron_variant	Intron 4 of 12	1		ENSP00000341071.4
ARHGEF3	ENST00000496106.5	c.114+50544T>C		intron_variant	Intron 2 of 10	2		ENSP00000420420.1
ARHGEF3	ENST00000473779.5	c.150+50544T>C		intron_variant	Intron 3 of 6	3		ENSP00000420402.1

Frequencies

GnomAD3 genomes AF: 0.626 AC: 95173 AN: 151992 Hom.: 30098 Cov.: 33

Gnomad AFR AF: 0.656

Gnomad AMI AF: 0.568

Gnomad AMR AF: 0.507

Gnomad ASJ AF: 0.550

Gnomad EAS AF: 0.630

Gnomad SAS AF: 0.520

Gnomad FIN AF: 0.716

Gnomad MID AF: 0.525

Gnomad NFE AF: 0.634

Gnomad OTH AF: 0.593

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

GnomAD4 genome AF: 0.626 AC: 95226 AN: 152110 Hom.: 30114 Cov.: 33 AF XY: 0.624 AC XY: 46358 AN XY: 74348

African (AFR) AF: 0.656 AC: 27217 AN: 41502

American (AMR) AF: 0.507 AC: 7748 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.550 AC: 1907 AN: 3466

East Asian (EAS) AF: 0.630 AC: 3242 AN: 5150

South Asian (SAS) AF: 0.521 AC: 2511 AN: 4820

European-Finnish (FIN) AF: 0.716 AC: 7577 AN: 10584

Middle Eastern (MID) AF: 0.517 AC: 152 AN: 294

European-Non Finnish (NFE) AF: 0.634 AC: 43111 AN: 67978

Other (OTH) AF: 0.589 AC: 1243 AN: 2112

Alfa AF: 0.625 Hom.: 104662

Bravo AF: 0.615

Asia WGS AF: 0.571 AC: 1984 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	4.9
DANN	Benign	0.70
PhyloP100		1.4
Mutation Taster		=99/1	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs12485738; hg19: chr3-56865776;