3-56958882-G-A

Variant names:

• chr3-56958882-G-A
• rs535956308
• ENST00000338458.8:c.70C>T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001377411.1(ARHGEF3):​c.-24C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000129 in 1,550,936 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: ARHGEF3 NM_001377411.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.40

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]

ARHGEF3-AS1 (HGNC:40083): (ARHGEF3 antisense RNA 1)

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.12214288).
• BS2: High AC in GnomAdExome4 at 17 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGEF3	NM_001377411.1	c.-24C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 2 of 12		NP_001364340.1
ARHGEF3	NM_001377412.1	c.-24C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 2 of 12		NP_001364341.1
ARHGEF3	XM_047448225.1	c.-24C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 3 of 13		XP_047304181.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARHGEF3	ENST00000338458.8	c.70C>T	p.Arg24Trp	missense_variant	Exon 3 of 13	1		ENSP00000341071.4
ARHGEF3	ENST00000468727.5	c.-24C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 2 of 8	3		ENSP00000417087.1
ARHGEF3	ENST00000473779.5	c.28C>T	p.Arg10Trp	missense_variant	Exon 2 of 7	3		ENSP00000420402.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152128 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000320 AC: 5 AN: 156396 Hom.: 0 AF XY: 0.0000241 AC XY: 2 AN XY: 82880

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000405

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000178

Gnomad NFE exome AF: 0.0000166

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000122 AC: 17 AN: 1398808 Hom.: 0 Cov.: 30 AF XY: 0.00000580 AC XY: 4 AN XY: 689966

Gnomad4 AFR exome AF: 0.0000633

Gnomad4 AMR exome AF: 0.0000560

Gnomad4 ASJ exome AF: 0.0000397

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000812

Gnomad4 NFE exome AF: 0.00000649

Gnomad4 OTH exome AF: 0.0000172

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152128 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74312

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 05, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.70C>T (p.R24W) alteration is located in exon 3 (coding exon 2) of the ARHGEF3 gene. This alteration results from a C to T substitution at nucleotide position 70, causing the arginine (R) at amino acid position 24 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.024	.;T;.
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.047
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.78	T;T;T
M_CAP	Benign	0.0083	T
MetaRNN	Benign	0.12	T;T;T
MetaSVM	Benign	-1.1	T
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.39	N;N;N
REVEL	Benign	0.13
Sift	Uncertain	0.026	D;D;D
Sift4G	Uncertain	0.033	D;.;D
Polyphen		0.99	D;.;.
Vest4		0.25
MutPred		0.21		Loss of glycosylation at P22 (P = 0.0152);.;Loss of glycosylation at P22 (P = 0.0152);
MVP		0.21
MPC		0.88
ClinPred		0.85	D
GERP RS		2.8
gMVP		0.48

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs535956308; hg19: chr3-56992910;