rs9657362

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_014629.4(ARHGEF10):c.1110G>C(p.Leu370Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.154 in 1,612,786 control chromosomes in the GnomAD database, including 21,612 homozygotes. 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 Benign (★★).

Frequency

Genomes: 𝑓 0.12 ( 1494 hom., cov: 32)

Exomes 𝑓: 0.16 ( 20118 hom. )

Consequence

ARHGEF10
NM_014629.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts U:1B:5

Conservation

PhyloP100: 0.730

Variant links:

Genes affected

ARHGEF10 (HGNC:14103): (Rho guanine nucleotide exchange factor 10) This gene encodes a Rho guanine nucleotide exchange factor (GEF). Rho GEFs regulate the activity of small Rho GTPases by stimulating the exchange of guanine diphosphate (GDP) for guanine triphosphate (GTP) and may play a role in neural morphogenesis. Mutations in this gene are associated with slowed nerve conduction velocity (SNCV). Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2015]

ARHGEF10 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0061654747).

BP6

Variant 8-1885635-G-C is Benign according to our data. Variant chr8-1885635-G-C is described in ClinVar as [Benign]. Clinvar id is 618536.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-1885635-G-C is described in Lovd as [Benign]. Variant chr8-1885635-G-C is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.272 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARHGEF10	NM_014629.4 linkuse as main transcript	c.1110G>C	p.Leu370Phe	missense_variant	11/29	ENST00000349830.8	NP_055444.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARHGEF10	ENST00000349830.8 linkuse as main transcript	c.1110G>C	p.Leu370Phe	missense_variant	11/29	1	NM_014629.4	ENSP00000340297	P4	O15013-5

Frequencies

GnomAD3 genomes

AF:

0.120

AC:

18297

AN:

151932

Hom.:

1496

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0324

Gnomad AMI

AF:

0.235

Gnomad AMR

AF:

0.143

Gnomad ASJ

AF:

0.0789

Gnomad EAS

AF:

0.284

Gnomad SAS

AF:

0.278

Gnomad FIN

AF:

0.106

Gnomad MID

AF:

0.165

Gnomad NFE

AF:

0.148

Gnomad OTH

AF:

0.109

GnomAD3 exomes

AF:

0.159

AC:

40013

AN:

251278

Hom.:

3902

AF XY:

0.167

AC XY:

22641

AN XY:

135852

show subpopulations

Gnomad AFR exome

AF:

0.0304

Gnomad AMR exome

AF:

0.141

Gnomad ASJ exome

AF:

0.0819

Gnomad EAS exome

AF:

0.292

Gnomad SAS exome

AF:

0.282

Gnomad FIN exome

AF:

0.121

Gnomad NFE exome

AF:

0.144

Gnomad OTH exome

AF:

0.143

GnomAD4 exome

AF:

0.158

AC:

230465

AN:

1460736

Hom.:

20118

Cov.:

AF XY:

0.162

AC XY:

117443

AN XY:

726732

show subpopulations

Gnomad4 AFR exome

AF:

0.0280

Gnomad4 AMR exome

AF:

0.142

Gnomad4 ASJ exome

AF:

0.0788

Gnomad4 EAS exome

AF:

0.286

Gnomad4 SAS exome

AF:

0.276

Gnomad4 FIN exome

AF:

0.121

Gnomad4 NFE exome

AF:

0.152

Gnomad4 OTH exome

AF:

0.156

GnomAD4 genome

AF:

0.120

AC:

18294

AN:

152050

Hom.:

1494

Cov.:

AF XY:

0.123

AC XY:

9104

AN XY:

74300

show subpopulations

Gnomad4 AFR

AF:

0.0323

Gnomad4 AMR

AF:

0.143

Gnomad4 ASJ

AF:

0.0789

Gnomad4 EAS

AF:

0.284

Gnomad4 SAS

AF:

0.278

Gnomad4 FIN

AF:

0.106

Gnomad4 NFE

AF:

0.148

Gnomad4 OTH

AF:

0.108

Alfa

AF:

0.108

Hom.:

357

Bravo

AF:

0.115

TwinsUK

AF:

0.153

AC:

568

ALSPAC

AF:

0.140

AC:

539

ESP6500AA

AF:

0.0372

AC:

164

ESP6500EA

AF:

0.144

AC:

1242

ExAC

AF:

0.159

AC:

19271

Asia WGS

AF:

0.239

AC:

828

AN:

3478

EpiCase

AF:

0.150

EpiControl

AF:

0.146

ClinVar

Significance: Benign

Submissions summary: Uncertain:1Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	This variant is associated with the following publications: (PMID: 25164601) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Charcot-Marie-Tooth disease

Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

Inherited Neuropathy Consortium

- -

Autosomal dominant slowed nerve conduction velocity

Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 29, 2023

- -

ARHGEF10-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 18, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.38

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.14

.;.;.;T;T;.

Eigen

Benign

-0.78

Eigen_PC

Benign

-0.95

FATHMM_MKL

Benign

0.42

MetaRNN

Benign

0.0062

T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.5

.;.;M;M;.;.

MutationTaster

Benign

0.79

P;P;P;P;P;P

PrimateAI

Benign

0.29

PROVEAN

Benign

-1.6

N;N;N;N;.;N

REVEL

Benign

0.23

Sift

Benign

0.20

T;T;T;T;.;T

Sift4G

Benign

0.19

T;T;T;T;T;T

Polyphen

0.71

P;D;.;D;.;.

Vest4

0.17

MutPred

0.42

.;.;Loss of stability (P = 0.1226);Loss of stability (P = 0.1226);.;.;

MPC

0.24

ClinPred

0.030

GERP RS

-4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.036

gMVP

0.24

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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