Variant 2-130916381-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_001367493.1(ARHGEF4):c.2435G>A(p.Gly812Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00123 in 1,535,482 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 8/11 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00095 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0013 ( 2 hom. )

Consequence

ARHGEF4
NM_001367493.1 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.0680

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 Benign. Variant got -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.007549405).

BP6

Variant 2-130916381-G-A is Benign according to our data. Variant chr2-130916381-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3025084.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
ARHGEF4	NM_001367493.1 linkuse as main transcript	c.2435G>A	p.Gly812Glu	missense_variant	2/14	ENST00000409359.7	NP_001354422.1
ARHGEF4	NM_015320.4 linkuse as main transcript	c.-789G>A		5_prime_UTR_variant	2/15		NP_056135.2
ARHGEF4	NM_001375900.1 linkuse as main transcript	c.40-14571G>A		intron_variant			NP_001362829.1
ARHGEF4	NM_001375901.1 linkuse as main transcript	c.-108-1016G>A		intron_variant			NP_001362830.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARHGEF4	ENST00000409359.7 linkuse as main transcript	c.2435G>A	p.Gly812Glu	missense_variant	2/14	5	NM_001367493.1	ENSP00000386794	P3
ARHGEF4	ENST00000526381.2 linkuse as main transcript	n.2643G>A		non_coding_transcript_exon_variant	2/4	2

Frequencies

GnomAD3 genomes

AF:

0.000953

AC:

145

AN:

152116

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000555

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000851

Gnomad ASJ

AF:

0.00346

Gnomad EAS

AF:

0.000194

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00138

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000929

AC:

119

AN:

128080

Hom.:

AF XY:

0.000867

AC XY:

AN XY:

70350

show subpopulations

Gnomad AFR exome

AF:

0.000838

Gnomad AMR exome

AF:

0.00112

Gnomad ASJ exome

AF:

0.00266

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000470

Gnomad FIN exome

AF:

0.000101

Gnomad NFE exome

AF:

0.00131

Gnomad OTH exome

AF:

0.00131

GnomAD4 exome

AF:

0.00126

AC:

1742

AN:

1383248

Hom.:

Cov.:

AF XY:

0.00127

AC XY:

866

AN XY:

681954

show subpopulations

Gnomad4 AFR exome

AF:

0.000578

Gnomad4 AMR exome

AF:

0.00132

Gnomad4 ASJ exome

AF:

0.00202

Gnomad4 EAS exome

AF:

0.0000281

Gnomad4 SAS exome

AF:

0.0000383

Gnomad4 FIN exome

AF:

0.0000707

Gnomad4 NFE exome

AF:

0.00143

Gnomad4 OTH exome

AF:

0.00131

GnomAD4 genome

AF:

0.000952

AC:

145

AN:

152234

Hom.:

Cov.:

AF XY:

0.000847

AC XY:

AN XY:

74424

show subpopulations

Gnomad4 AFR

AF:

0.000554

Gnomad4 AMR

AF:

0.000850

Gnomad4 ASJ

AF:

0.00346

Gnomad4 EAS

AF:

0.000194

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00138

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.00133

Hom.:

Bravo

AF:

0.00105

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000778

AC:

ExAC

AF:

0.000427

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Dec 01, 2023

ARHGEF4: BP4 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.55

CADD

Benign

5.3

DANN

Uncertain

0.99

DEOGEN2

Benign

0.012

Eigen

Benign

-0.89

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.022

LIST_S2

Benign

0.37

M_CAP

Uncertain

0.27

MetaRNN

Benign

0.0075

MetaSVM

Benign

-1.0

MutationTaster

Benign

1.0

REVEL

Benign

0.033

MVP

0.29

ClinPred

0.015

GERP RS

-2.0

Splicing

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