rs200779877

Positions:

chr8-1956817-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_014629.4(ARHGEF10):c.3589C>T(p.His1197Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000323 in 1,613,974 control chromosomes in the GnomAD database, including 3 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 Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00033 ( 3 hom. )

Consequence

ARHGEF10
NM_014629.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: 1.03

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:

KBTBD11-OT1 (HGNC:):

KBTBD11-OT1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.02002272).

BS2

High AC in GnomAd4 at 39 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARHGEF10	NM_014629.4 linkuse as main transcript	c.3589C>T	p.His1197Tyr	missense_variant	29/29	ENST00000349830.8	NP_055444.2	O15013-5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
ARHGEF10	ENST00000349830.8 linkuse as main transcript	c.3589C>T	p.His1197Tyr	missense_variant	29/29	1	NM_014629.4	ENSP00000340297.3	O15013-5
KBTBD11-OT1	ENST00000635855.1 linkuse as main transcript	n.*3543C>T		non_coding_transcript_exon_variant	30/30	5		ENSP00000489726.1	A0A1B0GTJ5
KBTBD11-OT1	ENST00000635855.1 linkuse as main transcript	n.*3543C>T		3_prime_UTR_variant	30/30	5		ENSP00000489726.1	A0A1B0GTJ5

Frequencies

GnomAD3 genomes

AF:

0.000256

AC:

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000659

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000326

AC:

AN:

251392

Hom.:

AF XY:

0.000324

AC XY:

AN XY:

135908

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.000739

Gnomad NFE exome

AF:

0.000493

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.000330

AC:

483

AN:

1461768

Hom.:

Cov.:

AF XY:

0.000340

AC XY:

247

AN XY:

727192

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000174

Gnomad4 FIN exome

AF:

0.000582

Gnomad4 NFE exome

AF:

0.000379

Gnomad4 OTH exome

AF:

0.000248

GnomAD4 genome

AF:

0.000256

AC:

AN:

152206

Hom.:

Cov.:

AF XY:

0.000242

AC XY:

AN XY:

74350

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000659

Gnomad4 NFE

AF:

0.000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000446

Hom.:

Bravo

AF:

0.000178

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000379

AC:

EpiCase

AF:

0.000709

EpiControl

AF:

0.000296

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 06, 2022	BP4 -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 09, 2023	This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 1197 of the ARHGEF10 protein (p.His1197Tyr). This variant is present in population databases (rs200779877, gnomAD 0.06%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with ARHGEF10-related conditions. ClinVar contains an entry for this variant (Variation ID: 377194). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ARHGEF10 protein function with a negative predictive value of 80%. 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Feb 06, 2017	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 12, 2024

The c.3589C>T (p.H1197Y) alteration is located in exon 29 (coding exon 28) of the ARHGEF10 gene. This alteration results from a C to T substitution at nucleotide position 3589, causing the histidine (H) at amino acid position 1197 to be replaced by a tyrosine (Y). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.47

CADD

Benign

0.95

DANN

Benign

0.57

DEOGEN2

Benign

0.016

.;.;.;T;.

Eigen

Benign

-0.95

Eigen_PC

Benign

-0.87

FATHMM_MKL

Benign

0.23

M_CAP

Benign

0.012

MetaRNN

Benign

0.020

T;T;T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.90

.;.;.;L;.

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.38

N;N;N;N;N

REVEL

Benign

0.12

Sift

Benign

1.0

T;T;T;T;T

Sift4G

Benign

0.75

T;T;T;T;T

Polyphen

0.065

B;B;.;.;.

Vest4

0.14

MVP

0.33

MPC

0.060

ClinPred

0.032

GERP RS

3.6

Varity_R

0.042

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