rs2294039

Variant names:

Variant summary

Our verdict is Benign. The variant received -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. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

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:7

Conservation

PhyloP100: 0.876

Publications

20 publications found

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 Gene-Disease associations (from GenCC):

autosomal dominant slowed nerve conduction velocity
Inheritance: Unknown, AD Classification: SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Orphanet
hereditary peripheral neuropathy
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
peripheral neuropathy
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ARHGEF10 links:

KBTBD11-OT1 (HGNC:):

KBTBD11-OT1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 439414.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 4668 Unknown,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGEF10	NM_014629.4 link	c.2098G>A	p.Val700Ile	missense_variant	Exon 18 of 29	ENST00000349830.8	NP_055444.2	O15013-5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ARHGEF10	ENST00000349830.8 link	c.2098G>A	p.Val700Ile	missense_variant	Exon 18 of 29	1	NM_014629.4	ENSP00000340297.3	O15013-5
KBTBD11-OT1	ENST00000635855.1 link	n.*2052G>A		non_coding_transcript_exon_variant	Exon 19 of 30	5		ENSP00000489726.1	A0A1B0GTJ5
KBTBD11-OT1	ENST00000635855.1 link	n.*2052G>A		3_prime_UTR_variant	Exon 19 of 30	5		ENSP00000489726.1	A0A1B0GTJ5

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

GnomAD2 exomes

AF:

0.0315

AC:

7915

AN:

251342

AF XY:

0.0324

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 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

African (AFR)

AF:

0.0155

AC:

519

AN:

33480

American (AMR)

AF:

0.0191

AC:

852

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0142

AC:

372

AN:

26134

East Asian (EAS)

AF:

0.0221

AC:

879

AN:

39700

South Asian (SAS)

AF:

0.0288

AC:

2484

AN:

86258

European-Finnish (FIN)

AF:

0.0427

AC:

2274

AN:

53296

Middle Eastern (MID)

AF:

0.00745

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0419

AC:

46604

AN:

1112006

Other (OTH)

AF:

0.0333

AC:

2012

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

3621

7241

10862

14482

18103

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1750

3500

5250

7000

8750

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0306

AC:

4668

AN:

152316

Hom.:

Cov.:

AF XY:

0.0309

AC XY:

2298

AN XY:

74478

show subpopulations

African (AFR)

AF:

0.0173

AC:

719

AN:

41584

American (AMR)

AF:

0.0260

AC:

398

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0121

AC:

AN:

3470

East Asian (EAS)

AF:

0.0193

AC:

100

AN:

5176

South Asian (SAS)

AF:

0.0278

AC:

134

AN:

4818

European-Finnish (FIN)

AF:

0.0435

AC:

462

AN:

10620

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0402

AC:

2735

AN:

68032

Other (OTH)

AF:

0.0242

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

232

464

696

928

1160

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

108

162

216

270

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0346

Hom.:

160

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:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal dominant slowed nerve conduction velocity

Benign:3

Oct 09, 2014

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 22, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 15, 2015

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

ARHGEF10-related disorder

Benign:1

Aug 29, 2024

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

(source)

DANN

Benign

0.85

DEOGEN2

Benign

0.013

.;.;.;T;.

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

MutationAssessor

Benign

1.6

.;.;.;L;.

PhyloP100

0.88

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

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over