2-130946624-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001367493.1(ARHGEF4):​c.3974C>A​(p.Thr1325Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,613,982 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

ARHGEF4
NM_001367493.1 missense

Scores

19

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -2.59
Variant links:
Genes affected
ARHGEF4 (HGNC:684): (Rho guanine nucleotide exchange factor 4) Rho GTPases play a fundamental role in numerous cellular processes that are initiated by extracellular stimuli that work through G protein coupled receptors. The protein encoded by this gene may form complex with G proteins and stimulate Rho-dependent signals. Multiple alternatively spliced transcript variants encoding different isoforms have been found, but the full-length nature of some variants has not been determined. [provided by RefSeq, Jun 2013]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.12732953).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ARHGEF4NM_001367493.1 linkc.3974C>A p.Thr1325Lys missense_variant Exon 4 of 14 ENST00000409359.7 NP_001354422.1
ARHGEF4NM_001375900.1 linkc.461C>A p.Thr154Lys missense_variant Exon 3 of 13 NP_001362829.1
ARHGEF4NM_015320.4 linkc.416C>A p.Thr139Lys missense_variant Exon 5 of 15 NP_056135.2 Q9NR80-1Q9NTG0
ARHGEF4NM_001375901.1 linkc.305C>A p.Thr102Lys missense_variant Exon 6 of 16 NP_001362830.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ARHGEF4ENST00000409359.7 linkc.3974C>A p.Thr1325Lys missense_variant Exon 4 of 14 5 NM_001367493.1 ENSP00000386794.3 E7EV07

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152224
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000796
AC:
2
AN:
251404
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135862
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000176
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000116
AC:
17
AN:
1461758
Hom.:
0
Cov.:
30
AF XY:
0.0000124
AC XY:
9
AN XY:
727170
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000153
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152224
Hom.:
0
Cov.:
32
AF XY:
0.0000134
AC XY:
1
AN XY:
74368
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000378

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Aug 04, 2023
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.416C>A (p.T139K) alteration is located in exon 4 (coding exon 2) of the ARHGEF4 gene. This alteration results from a C to A substitution at nucleotide position 416, causing the threonine (T) at amino acid position 139 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
0.078
BayesDel_addAF
Benign
-0.14
T
BayesDel_noAF
Benign
-0.44
CADD
Benign
4.0
DANN
Benign
0.49
DEOGEN2
Benign
0.0067
T;T;.;.;T;.
Eigen
Benign
-1.8
Eigen_PC
Benign
-2.0
FATHMM_MKL
Benign
0.011
N
LIST_S2
Benign
0.68
T;T;T;T;T;T
M_CAP
Benign
0.050
D
MetaRNN
Benign
0.13
T;T;T;T;T;T
MetaSVM
Benign
-0.80
T
MutationAssessor
Benign
1.4
.;L;.;.;.;L
PrimateAI
Benign
0.44
T
PROVEAN
Benign
0.45
.;N;.;N;N;N
REVEL
Benign
0.12
Sift
Benign
0.12
.;T;.;T;T;T
Sift4G
Benign
0.96
.;T;T;T;T;T
Polyphen
0.13, 0.79
.;B;.;.;.;P
Vest4
0.25, 0.28, 0.28, 0.25
MVP
0.62
MPC
0.15
ClinPred
0.076
T
GERP RS
-8.7
Varity_R
0.050
gMVP
0.27

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: rs1223136947; hg19: chr2-131704197; API