rs2294039

Positions:

chr8-1909425-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_014629.4(ARHGEF10):c.2098G>A(p.Val700Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0376 in 1,614,074 control chromosomes in the GnomAD database, including 1,272 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.031 ( 77 hom., cov: 33)

Exomes 𝑓: 0.038 ( 1195 hom. )

Consequence

ARHGEF10
NM_014629.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.876

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=0.0030667782).

BP6

Variant 8-1909425-G-A is Benign according to our data. Variant chr8-1909425-G-A is described in ClinVar as [Benign]. Clinvar id is 439414.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-1909425-G-A is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0306 (4668/152316) while in subpopulation NFE AF= 0.0402 (2735/68032). AF 95% confidence interval is 0.0389. There are 77 homozygotes in gnomad4. There are 2298 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 4668 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARHGEF10	NM_014629.4 linkuse as main transcript	c.2098G>A	p.Val700Ile	missense_variant	18/29	ENST00000349830.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARHGEF10	ENST00000349830.8 linkuse as main transcript	c.2098G>A	p.Val700Ile	missense_variant	18/29	1	NM_014629.4	P4	O15013-5

Frequencies

GnomAD3 genomes

AF:

0.0306

AC:

4663

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0172

Gnomad AMI

AF:

0.0252

Gnomad AMR

AF:

0.0260

Gnomad ASJ

AF:

0.0121

Gnomad EAS

AF:

0.0193

Gnomad SAS

AF:

0.0278

Gnomad FIN

AF:

0.0435

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0402

Gnomad OTH

AF:

0.0244

GnomAD3 exomes

AF:

0.0315

AC:

7915

AN:

251342

Hom.:

152

AF XY:

0.0324

AC XY:

4403

AN XY:

135904

show subpopulations

Gnomad AFR exome

AF:

0.0148

Gnomad AMR exome

AF:

0.0176

Gnomad ASJ exome

AF:

0.0147

Gnomad EAS exome

AF:

0.0193

Gnomad SAS exome

AF:

0.0279

Gnomad FIN exome

AF:

0.0433

Gnomad NFE exome

AF:

0.0404

Gnomad OTH exome

AF:

0.0287

GnomAD4 exome

AF:

0.0383

AC:

56039

AN:

1461758

Hom.:

1195

Cov.:

AF XY:

0.0382

AC XY:

27775

AN XY:

727190

show subpopulations

Gnomad4 AFR exome

AF:

0.0155

Gnomad4 AMR exome

AF:

0.0191

Gnomad4 ASJ exome

AF:

0.0142

Gnomad4 EAS exome

AF:

0.0221

Gnomad4 SAS exome

AF:

0.0288

Gnomad4 FIN exome

AF:

0.0427

Gnomad4 NFE exome

AF:

0.0419

Gnomad4 OTH exome

AF:

0.0333

GnomAD4 genome

AF:

0.0306

AC:

4668

AN:

152316

Hom.:

Cov.:

AF XY:

0.0309

AC XY:

2298

AN XY:

74478

show subpopulations

Gnomad4 AFR

AF:

0.0173

Gnomad4 AMR

AF:

0.0260

Gnomad4 ASJ

AF:

0.0121

Gnomad4 EAS

AF:

0.0193

Gnomad4 SAS

AF:

0.0278

Gnomad4 FIN

AF:

0.0435

Gnomad4 NFE

AF:

0.0402

Gnomad4 OTH

AF:

0.0242

Alfa

AF:

0.0355

Hom.:

124

Bravo

AF:

0.0281

TwinsUK

AF:

0.0461

AC:

171

ALSPAC

AF:

0.0394

AC:

152

ESP6500AA

AF:

0.0159

AC:

ESP6500EA

AF:

0.0401

AC:

345

ExAC

AF:

0.0324

AC:

3938

Asia WGS

AF:

0.0210

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal dominant slowed nerve conduction velocity

Benign:3

Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Jan 15, 2015	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -

not specified

Benign:1

Benign, no assertion criteria provided

clinical testing

Clinical Genetics, Academic Medical Center

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

ARHGEF10-related disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 05, 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

0.073

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.60

CADD

Benign

5.4

DANN

Benign

0.85

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.11

MetaRNN

Benign

0.0031

T;T;T;T;T

MetaSVM

Benign

-1.1

MutationTaster

Benign

1.0

N;N;N;N;N

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.25

N;N;N;N;N

REVEL

Benign

0.067

Sift

Benign

0.41

T;T;T;T;T

Sift4G

Benign

0.63

T;T;T;T;T

Polyphen

0.0050

B;B;.;B;.

Vest4

0.056

MPC

0.030

ClinPred

0.0022

GERP RS

2.0

Varity_R

0.014

gMVP

0.17

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