dbSNP rs1383049756: ARHGEF4:p.Pro1241Arg (chr2-130931121-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001367493.1(ARHGEF4):c.3722C>G(p.Pro1241Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,840 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1241L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

ARHGEF4
NM_001367493.1 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.833

Publications

0 publications found

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]

ARHGEF4 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.14698267).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001367493.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ARHGEF4	NM_001367493.1	MANE Select	c.3722C>G	p.Pro1241Arg	missense	Exon 3 of 14	NP_001354422.1	E7EV07
ARHGEF4	NM_001375900.1		c.209C>G	p.Pro70Arg	missense	Exon 2 of 13	NP_001362829.1
ARHGEF4	NM_015320.4		c.164C>G	p.Pro55Arg	missense	Exon 4 of 15	NP_056135.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ARHGEF4	ENST00000409359.7	TSL:5 MANE Select	c.3722C>G	p.Pro1241Arg	missense	Exon 3 of 14	ENSP00000386794.3	E7EV07
ARHGEF4	ENST00000392953.8	TSL:1	c.236C>G	p.Pro79Arg	missense	Exon 2 of 12	ENSP00000376680.5	A0A0C4DFY6
ARHGEF4	ENST00000918336.1		c.3722C>G	p.Pro1241Arg	missense	Exon 3 of 14	ENSP00000588395.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000400

AC:

AN:

249988

AF XY:

0.00000739

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461840

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727220

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111992

Other (OTH)

AF:

0.00

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.33

CADD

Benign

8.6

(source)

DANN

Benign

0.91

DEOGEN2

Benign

0.022

Eigen

Benign

-0.49

Eigen_PC

Benign

-0.58

FATHMM_MKL

Benign

0.044

LIST_S2

Benign

0.76

M_CAP

Benign

0.082

MetaRNN

Benign

0.15

MetaSVM

Benign

-0.65

PhyloP100

0.83

PrimateAI

Benign

0.27

PROVEAN

Benign

-0.99

REVEL

Benign

0.091

Sift

Uncertain

0.027

Sift4G

Benign

0.67

Polyphen

0.43

Vest4

0.11

MVP

0.81

MPC

0.13

ClinPred

0.15

GERP RS

3.8

Varity_R

0.054

gMVP

0.054

Mutation Taster

=88/12

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over