8-1923017-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_014629.4(ARHGEF10):c.2197C>T(p.His733Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00175 in 1,613,580 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H733R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0012 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0018 ( 4 hom. )

Consequence

ARHGEF10
NM_014629.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:2

Conservation

PhyloP100: 4.39

Publications

4 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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.02310282).

BP6

Variant 8-1923017-C-T is Benign according to our data. Variant chr8-1923017-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 157538.

BS2

High AC in GnomAd4 at 178 Unknown,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGEF10	NM_014629.4 link	c.2197C>T	p.His733Tyr	missense_variant	Exon 19 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.2197C>T	p.His733Tyr	missense_variant	Exon 19 of 29	1	NM_014629.4	ENSP00000340297.3	O15013-5
KBTBD11-OT1	ENST00000635855.1 link	n.*2151C>T		non_coding_transcript_exon_variant	Exon 20 of 30	5		ENSP00000489726.1	A0A1B0GTJ5
KBTBD11-OT1	ENST00000635855.1 link	n.*2151C>T		3_prime_UTR_variant	Exon 20 of 30	5		ENSP00000489726.1	A0A1B0GTJ5

Frequencies

GnomAD3 genomes

AF:

0.00117

AC:

178

AN:

152092

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000314

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.000283

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00222

Gnomad OTH

AF:

0.000480

GnomAD2 exomes

AF:

0.00107

AC:

268

AN:

251168

AF XY:

0.000994

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.000463

Gnomad ASJ exome

AF:

0.000992

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000140

Gnomad NFE exome

AF:

0.00191

Gnomad OTH exome

AF:

0.000816

GnomAD4 exome

AF:

0.00181

AC:

2642

AN:

1461372

Hom.:

Cov.:

AF XY:

0.00176

AC XY:

1282

AN XY:

726996

show subpopulations

African (AFR)

AF:

0.000209

AC:

AN:

33468

American (AMR)

AF:

0.000514

AC:

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.00119

AC:

AN:

26126

East Asian (EAS)

AF:

0.00

AC:

AN:

39650

South Asian (SAS)

AF:

0.000568

AC:

AN:

86226

European-Finnish (FIN)

AF:

0.000395

AC:

AN:

53224

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5694

European-Non Finnish (NFE)

AF:

0.00217

AC:

2415

AN:

1111890

Other (OTH)

AF:

0.00159

AC:

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.440

Heterozygous variant carriers

134

268

403

537

671

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

176

264

352

440

<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:

0.00117

AC:

178

AN:

152208

Hom.:

Cov.:

AF XY:

0.000900

AC XY:

AN XY:

74432

show subpopulations

African (AFR)

AF:

0.000313

AC:

AN:

41536

American (AMR)

AF:

0.000392

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.000865

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5164

South Asian (SAS)

AF:

0.000207

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.000283

AC:

AN:

10594

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00222

AC:

151

AN:

68018

Other (OTH)

AF:

0.000475

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

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:

0.00162

Hom.:

Bravo

AF:

0.00121

TwinsUK

AF:

0.00324

AC:

ALSPAC

AF:

0.00259

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00163

AC:

ExAC

AF:

0.00108

AC:

131

Asia WGS

AF:

0.000578

AC:

AN:

3476

EpiCase

AF:

0.00142

EpiControl

AF:

0.00148

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Jan 14, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 24, 2022

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ARHGEF10: BS1, BS2 -

Charcot-Marie-Tooth disease

Uncertain:1

Nov 01, 2013

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

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:research

- -

Autosomal dominant slowed nerve conduction velocity

Uncertain:1

Oct 02, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.20

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.31

.;.;.;T;.

Eigen

Uncertain

0.20

Eigen_PC

Benign

0.12

FATHMM_MKL

Uncertain

0.96

M_CAP

Benign

0.060

MetaRNN

Benign

0.023

T;T;T;T;T

MetaSVM

Benign

-0.42

MutationAssessor

Uncertain

2.7

.;.;.;M;.

PhyloP100

4.4

PrimateAI

Uncertain

0.67

PROVEAN

Pathogenic

-4.7

D;D;D;D;D

REVEL

Uncertain

0.36

Sift

Benign

0.13

T;T;T;T;T

Sift4G

Benign

0.11

T;T;T;T;T

Polyphen

0.83

P;D;.;D;.

Vest4

0.43

MVP

0.74

MPC

0.052

ClinPred

0.20

GERP RS

4.0

Varity_R

0.24

gMVP

0.62

Mutation Taster

=99/1

polymorphism

(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