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GeneBe

3-56729276-G-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_019555.3(ARHGEF3):​c.1575C>A​(p.Asn525Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000869 in 1,610,436 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00013 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000082 ( 0 hom. )

Consequence

ARHGEF3
NM_019555.3 missense

Scores

1
2
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -2.18
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.03406006).
BS2
High AC in GnomAd4 at 20 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
ARHGEF3NM_019555.3 linkuse as main transcriptc.1575C>A p.Asn525Lys missense_variant 10/10 ENST00000296315.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
ARHGEF3ENST00000296315.8 linkuse as main transcriptc.1575C>A p.Asn525Lys missense_variant 10/101 NM_019555.3 P1Q9NR81-1

Frequencies

GnomAD3 genomes
AF:
0.000131
AC:
20
AN:
152202
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000482
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
Gnomad ASJ
AF:
0.00144
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000147
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.0000926
AC:
23
AN:
248404
Hom.:
0
AF XY:
0.000104
AC XY:
14
AN XY:
134116
show subpopulations
Gnomad AFR exome
AF:
0.0000616
Gnomad AMR exome
AF:
0.0000871
Gnomad ASJ exome
AF:
0.000616
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000333
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000981
Gnomad OTH exome
AF:
0.000165
GnomAD4 exome
AF:
0.0000823
AC:
120
AN:
1458116
Hom.:
0
Cov.:
30
AF XY:
0.0000855
AC XY:
62
AN XY:
724994
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000897
Gnomad4 ASJ exome
AF:
0.000658
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000117
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000811
Gnomad4 OTH exome
AF:
0.000133
GnomAD4 genome
AF:
0.000131
AC:
20
AN:
152320
Hom.:
0
Cov.:
33
AF XY:
0.000134
AC XY:
10
AN XY:
74478
show subpopulations
Gnomad4 AFR
AF:
0.0000481
Gnomad4 AMR
AF:
0.000131
Gnomad4 ASJ
AF:
0.00144
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000147
Gnomad4 OTH
AF:
0.000473
Alfa
AF:
0.000164
Hom.:
0
Bravo
AF:
0.0000869
TwinsUK
AF:
0.00
AC:
0
ALSPAC
AF:
0.000259
AC:
1
ExAC
AF:
0.0000741
AC:
9

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsMar 06, 2023The c.1671C>A (p.N557K) alteration is located in exon 13 (coding exon 12) of the ARHGEF3 gene. This alteration results from a C to A substitution at nucleotide position 1671, causing the asparagine (N) at amino acid position 557 to be replaced by a lysine (K). 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
AlphaMissense
Benign
0.13
BayesDel_addAF
Benign
-0.45
T
BayesDel_noAF
Benign
-0.65
CADD
Benign
0.074
DANN
Benign
0.96
DEOGEN2
Benign
0.0094
T;.;.;T;T
Eigen
Benign
-1.3
Eigen_PC
Benign
-1.4
FATHMM_MKL
Benign
0.18
N
LIST_S2
Benign
0.75
T;T;T;T;T
M_CAP
Benign
0.0085
T
MetaRNN
Benign
0.034
T;T;T;T;T
MetaSVM
Benign
-0.93
T
MutationAssessor
Benign
0.90
L;.;.;.;.
MutationTaster
Benign
0.74
D;D;D;D;D
PrimateAI
Uncertain
0.55
T
PROVEAN
Benign
-0.87
N;N;N;N;N
REVEL
Benign
0.051
Sift
Uncertain
0.0070
D;D;D;D;D
Sift4G
Pathogenic
0.0
D;D;D;D;D
Polyphen
0.089
B;B;B;B;P
Vest4
0.28
MutPred
0.13
.;.;Gain of ubiquitination at N531 (P = 0.0069);Gain of ubiquitination at N531 (P = 0.0069);.;
MVP
0.32
MPC
0.18
ClinPred
0.040
T
GERP RS
-6.6
Varity_R
0.076
gMVP
0.20

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs747749503; hg19: chr3-56763304; API