8-1882687-G-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_014629.4(ARHGEF10):c.1013G>C(p.Arg338Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000027 in 1,557,436 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. R338R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000027 ( 0 hom. )

Consequence

ARHGEF10
NM_014629.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:4B:1

Conservation

PhyloP100: 1.74

Publications

3 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 -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.07315242).

BP6

Variant 8-1882687-G-C is Benign according to our data. Variant chr8-1882687-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 156013.

BS2

High AC in GnomAdExome4 at 38 Unknown,AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014629.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ARHGEF10	NM_014629.4	MANE Select	c.1013G>C	p.Arg338Thr	missense	Exon 10 of 29	NP_055444.2
ARHGEF10	NM_001438091.1		c.1016G>C	p.Arg339Thr	missense	Exon 10 of 29	NP_001425020.1
ARHGEF10	NM_001308153.3		c.1016G>C	p.Arg339Thr	missense	Exon 11 of 30	NP_001295082.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ARHGEF10	ENST00000349830.8	TSL:1 MANE Select	c.1013G>C	p.Arg338Thr	missense	Exon 10 of 29	ENSP00000340297.3
ARHGEF10	ENST00000518288.5	TSL:1	c.1088G>C	p.Arg363Thr	missense	Exon 11 of 30	ENSP00000431012.1
ARHGEF10	ENST00000520359.5	TSL:1	c.899G>C	p.Arg300Thr	missense	Exon 9 of 28	ENSP00000427909.1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000181

AC:

AN:

165732

AF XY:

0.0000229

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000459

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000270

AC:

AN:

1405222

Hom.:

Cov.:

AF XY:

0.0000360

AC XY:

AN XY:

693552

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32152

American (AMR)

AF:

0.00

AC:

AN:

36540

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25238

East Asian (EAS)

AF:

0.00

AC:

AN:

36570

South Asian (SAS)

AF:

0.00

AC:

AN:

79678

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49150

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5704

European-Non Finnish (NFE)

AF:

0.0000314

AC:

AN:

1081984

Other (OTH)

AF:

0.0000687

AC:

AN:

58206

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.0000263

AC:

AN:

152214

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74372

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41466

American (AMR)

AF:

0.00

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4838

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68036

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000100

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.0000359

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:4Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:1

Jul 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ARHGEF10: BP4

Oct 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with threonine, which is neutral and polar, at codon 338 of the ARHGEF10 protein (p.Arg338Thr). This variant is present in population databases (rs587777712, gnomAD 0.005%). This missense change has been observed in individual(s) with Charcot-Marie-Tooth disease (PMID: 25025039). ClinVar contains an entry for this variant (Variation ID: 156013). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Aug 12, 2016

OMIM

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:literature only

Autosomal dominant slowed nerve conduction velocity

Uncertain:2

Jan 06, 2016

Inherited Neuropathy Consortium Ii, University Of Miami

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:literature only

Oct 11, 2019

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Charcot-Marie-Tooth disease

Pathogenic:1

Nov 01, 2013

Dept. of Medical Genetics, Telemark Hospital Trust, Telemark Hospital Trust

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:research

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.61

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.40

CADD

Benign

8.7

(source)

DANN

Benign

0.73

DEOGEN2

Benign

0.040

Eigen

Benign

-1.0

Eigen_PC

Benign

-0.96

FATHMM_MKL

Uncertain

0.85

M_CAP

Benign

0.027

MetaRNN

Benign

0.073

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.4

PhyloP100

1.7

PrimateAI

Benign

0.41

PROVEAN

Benign

-2.3

REVEL

Benign

0.096

Sift

Benign

0.055

Sift4G

Benign

0.071

Polyphen

0.0070

Vest4

0.27

MVP

0.26

MPC

0.097

ClinPred

0.064

GERP RS

0.17

PromoterAI

0.033

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.088

gMVP

0.18

Mutation Taster

=91/9

disease causing (ClinVar)

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over