Variant 2-130931121-C-T details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_001367493.1(ARHGEF4):c.3722C>T(p.Pro1241Leu) 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. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

ARHGEF4
NM_001367493.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.833

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 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=0.09640196).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
ARHGEF4	NM_001367493.1 linkuse as main transcript	c.3722C>T	p.Pro1241Leu	missense_variant	3/14	ENST00000409359.7	NP_001354422.1
ARHGEF4	NM_001375900.1 linkuse as main transcript	c.209C>T	p.Pro70Leu	missense_variant	2/13		NP_001362829.1
ARHGEF4	NM_015320.4 linkuse as main transcript	c.164C>T	p.Pro55Leu	missense_variant	4/15		NP_056135.2
ARHGEF4	NM_001375901.1 linkuse as main transcript	c.53C>T	p.Pro18Leu	missense_variant	5/16		NP_001362830.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARHGEF4	ENST00000409359.7 linkuse as main transcript	c.3722C>T	p.Pro1241Leu	missense_variant	3/14	5	NM_001367493.1	ENSP00000386794	P3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000400

AC:

AN:

249988

Hom.:

AF XY:

0.00000739

AC XY:

AN XY:

135272

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS 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

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

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 submitter

clinical testing

Ambry Genetics

Dec 01, 2023

The c.164C>T (p.P55L) alteration is located in exon 3 (coding exon 1) of the ARHGEF4 gene. This alteration results from a C to T substitution at nucleotide position 164, causing the proline (P) at amino acid position 55 to be replaced by a leucine (L). 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

0.075

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.41

CADD

Benign

DANN

Benign

0.70

DEOGEN2

Benign

0.026

T;T;.;.;T;.

Eigen

Benign

-0.63

Eigen_PC

Benign

-0.68

FATHMM_MKL

Benign

0.025

LIST_S2

Benign

0.76

T;T;T;T;T;T

M_CAP

Benign

0.073

MetaRNN

Benign

0.096

T;T;T;T;T;T

MetaSVM

Benign

-0.70

MutationTaster

Benign

1.0

N;N;N;N;N;N

PrimateAI

Benign

0.27

PROVEAN

Benign

-1.0

.;N;.;N;N;N

REVEL

Benign

0.044

Sift

Benign

0.77

.;T;.;T;T;T

Sift4G

Benign

0.92

.;T;T;T;T;T

Polyphen

0.099, 0.25

.;B;.;.;.;B

Vest4

0.085, 0.12, 0.11, 0.12

MVP

0.77

MPC

0.12

ClinPred

0.066

GERP RS

3.8

Varity_R

0.038

gMVP

0.060

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over