chr3-56789338-A-G

Variant names:

• chr3-56789338-A-G
• rs983739
• NM_019555.3:c.96+12365T>C

Variant summary

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

The NM_019555.3(ARHGEF3):​c.96+12365T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.667 in 152,044 control chromosomes in the GnomAD database, including 34,919 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 0.67 (34919 hom., cov: 32)
• Consequence: ARHGEF3 NM_019555.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.278
• Publications: 3 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=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.913 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGEF3	NM_019555.3	c.96+12365T>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.96+12365T>C		intron_variant	Intron 1 of 9	1	NM_019555.3	ENSP00000296315.3

Frequencies

GnomAD3 genomes AF: 0.667 AC: 101260 AN: 151926 Hom.: 34868 Cov.: 32

Gnomad AFR AF: 0.830

Gnomad AMI AF: 0.494

Gnomad AMR AF: 0.605

Gnomad ASJ AF: 0.667

Gnomad EAS AF: 0.934

Gnomad SAS AF: 0.651

Gnomad FIN AF: 0.532

Gnomad MID AF: 0.701

Gnomad NFE AF: 0.583

Gnomad OTH AF: 0.702

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

GnomAD4 genome AF: 0.667 AC: 101364 AN: 152044 Hom.: 34919 Cov.: 32 AF XY: 0.664 AC XY: 49344 AN XY: 74332

African (AFR) AF: 0.831 AC: 34455 AN: 41478

American (AMR) AF: 0.605 AC: 9236 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.667 AC: 2313 AN: 3470

East Asian (EAS) AF: 0.935 AC: 4841 AN: 5178

South Asian (SAS) AF: 0.650 AC: 3134 AN: 4818

European-Finnish (FIN) AF: 0.532 AC: 5612 AN: 10550

Middle Eastern (MID) AF: 0.719 AC: 210 AN: 292

European-Non Finnish (NFE) AF: 0.583 AC: 39626 AN: 67966

Other (OTH) AF: 0.705 AC: 1489 AN: 2112

Alfa AF: 0.637 Hom.: 6009

Bravo AF: 0.680

Asia WGS AF: 0.783 AC: 2721 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	0.62
PhyloP100		-0.28
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs983739; hg19: chr3-56823366;