8-1882687-G-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). 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

Uncertain significance criteria provided, multiple submitters, no conflicts P:1U:4

Conservation

PhyloP100: 1.74

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 Likely_benign. Variant got -2 ACMG points.

BP4

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARHGEF10	NM_014629.4 linkuse as main transcript	c.1013G>C	p.Arg338Thr	missense_variant	10/29	ENST00000349830.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARHGEF10	ENST00000349830.8 linkuse as main transcript	c.1013G>C	p.Arg338Thr	missense_variant	10/29	1	NM_014629.4	P4	O15013-5

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

GnomAD3 exomes

AF:

0.0000181

AC:

AN:

165732

Hom.:

AF XY:

0.0000229

AC XY:

AN XY:

87494

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 SAS 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

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000314

Gnomad4 OTH exome

AF:

0.0000687

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152214

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74372

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000100

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.0000359

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal dominant slowed nerve conduction velocity

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 11, 2019	- -
Uncertain significance, no assertion criteria provided	literature only	Inherited Neuropathy Consortium Ii, University Of Miami	Jan 06, 2016	- -

not provided

Uncertain:2

Uncertain significance, no assertion criteria provided	literature only	OMIM	Aug 12, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Aug 16, 2022	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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 156013). This missense change has been observed in individual(s) with Charcot-Marie-Tooth disease (PMID: 25025039). This variant is present in population databases (rs587777712, gnomAD 0.005%). 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). -

Charcot-Marie-Tooth disease

Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

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

Nov 01, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.61

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.40

Cadd

Benign

8.7

Dann

Benign

0.73

Eigen

Benign

-1.0

Eigen_PC

Benign

-0.96

FATHMM_MKL

Uncertain

0.85

M_CAP

Benign

0.027

MetaRNN

Benign

0.073

T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationTaster

Benign

1.0

N;N;N;N;N;N

PrimateAI

Benign

0.41

PROVEAN

Benign

-2.3

N;N;N;N;.;D

REVEL

Benign

0.096

Sift

Benign

0.055

T;T;T;T;.;T

Sift4G

Benign

0.071

T;T;T;T;T;T

Polyphen

0.0070

B;B;.;B;.;.

Vest4

0.27

MVP

0.26

MPC

0.097

ClinPred

0.064

GERP RS

0.17

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.088

gMVP

0.18

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