3-56775600-A-G

Variant names:

• chr3-56775600-A-G
• rs7646054
• ENST00000413728.6:c.-487T>C

Variant summary

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

The NM_001128616.2(ARHGEF3):​c.-487T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.577 in 985,346 control chromosomes in the GnomAD database, including 165,883 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 (30381 hom., cov: 32)
  • Exomes 𝑓: 0.57 (135502 hom.)
• Consequence: ARHGEF3 NM_001128616.2 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.184

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=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.803 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGEF3	NM_019555.3	c.97-1784T>C		intron_variant	Intron 1 of 9	ENST00000296315.8	NP_062455.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARHGEF3	ENST00000296315.8	c.97-1784T>C		intron_variant	Intron 1 of 9	1	NM_019555.3	ENSP00000296315.3

Frequencies

GnomAD3 genomes AF: 0.626 AC: 95127 AN: 151940 Hom.: 30358 Cov.: 32

Gnomad AFR AF: 0.731

Gnomad AMI AF: 0.492

Gnomad AMR AF: 0.546

Gnomad ASJ AF: 0.654

Gnomad EAS AF: 0.822

Gnomad SAS AF: 0.580

Gnomad FIN AF: 0.531

Gnomad MID AF: 0.684

Gnomad NFE AF: 0.582

Gnomad OTH AF: 0.666

GnomAD4 exome AF: 0.569 AC: 473851 AN: 833288 Hom.: 135502 Cov.: 32 AF XY: 0.568 AC XY: 218733 AN XY: 384832

Gnomad4 AFR exome AF: 0.738

Gnomad4 AMR exome AF: 0.529

Gnomad4 ASJ exome AF: 0.642

Gnomad4 EAS exome AF: 0.830

Gnomad4 SAS exome AF: 0.555

Gnomad4 FIN exome AF: 0.503

Gnomad4 NFE exome AF: 0.563

Gnomad4 OTH exome AF: 0.581

GnomAD4 genome AF: 0.626 AC: 95183 AN: 152058 Hom.: 30381 Cov.: 32 AF XY: 0.622 AC XY: 46255 AN XY: 74338

Gnomad4 AFR AF: 0.731

Gnomad4 AMR AF: 0.545

Gnomad4 ASJ AF: 0.654

Gnomad4 EAS AF: 0.823

Gnomad4 SAS AF: 0.579

Gnomad4 FIN AF: 0.531

Gnomad4 NFE AF: 0.582

Gnomad4 OTH AF: 0.668

Alfa AF: 0.598 Hom.: 54144

Bravo AF: 0.631

Asia WGS AF: 0.701 AC: 2436 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	2.9
DANN	Benign	0.50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs7646054; hg19: chr3-56809628;