rs9657362

chr8-1885635-G-Cchr8-1885635-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_014629.4(ARHGEF10):c.1110G>C(p.Leu370Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.154 in 1,612,786 control chromosomes in the GnomAD database, including 21,612 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1494 hom., cov: 32)
  • Exomes 𝑓: 0.16 (20118 hom.)
• Consequence: ARHGEF10 NM_014629.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts U:1 B:4
• Conservation: PhyloP100: 0.730

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0061654747).
• BP6: Variant 8-1885635-G-C is Benign according to our data. Variant chr8-1885635-G-C is described in ClinVar as [Benign]. Clinvar id is 618536.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-1885635-G-C is described in Lovd as [Benign]. Variant chr8-1885635-G-C is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.272 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARHGEF10	NM_014629.4	c.1110G>C	p.Leu370Phe	missense_variant	11/29	ENST00000349830.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARHGEF10	ENST00000349830.8	c.1110G>C	p.Leu370Phe	missense_variant	11/29	1	NM_014629.4	P4

Frequencies

GnomAD3 genomes AF: 0.120 AC: 18297 AN: 151932 Hom.: 1496 Cov.: 32

Gnomad AFR AF: 0.0324

Gnomad AMI AF: 0.235

Gnomad AMR AF: 0.143

Gnomad ASJ AF: 0.0789

Gnomad EAS AF: 0.284

Gnomad SAS AF: 0.278

Gnomad FIN AF: 0.106

Gnomad MID AF: 0.165

Gnomad NFE AF: 0.148

Gnomad OTH AF: 0.109

GnomAD3 exomes AF: 0.159 AC: 40013 AN: 251278 Hom.: 3902 AF XY: 0.167 AC XY: 22641 AN XY: 135852

Gnomad AFR exome AF: 0.0304

Gnomad AMR exome AF: 0.141

Gnomad ASJ exome AF: 0.0819

Gnomad EAS exome AF: 0.292

Gnomad SAS exome AF: 0.282

Gnomad FIN exome AF: 0.121

Gnomad NFE exome AF: 0.144

Gnomad OTH exome AF: 0.143

GnomAD4 exome AF: 0.158 AC: 230465 AN: 1460736 Hom.: 20118 Cov.: 32 AF XY: 0.162 AC XY: 117443 AN XY: 726732

Gnomad4 AFR exome AF: 0.0280

Gnomad4 AMR exome AF: 0.142

Gnomad4 ASJ exome AF: 0.0788

Gnomad4 EAS exome AF: 0.286

Gnomad4 SAS exome AF: 0.276

Gnomad4 FIN exome AF: 0.121

Gnomad4 NFE exome AF: 0.152

Gnomad4 OTH exome AF: 0.156

GnomAD4 genome AF: 0.120 AC: 18294 AN: 152050 Hom.: 1494 Cov.: 32 AF XY: 0.123 AC XY: 9104 AN XY: 74300

Gnomad4 AFR AF: 0.0323

Gnomad4 AMR AF: 0.143

Gnomad4 ASJ AF: 0.0789

Gnomad4 EAS AF: 0.284

Gnomad4 SAS AF: 0.278

Gnomad4 FIN AF: 0.106

Gnomad4 NFE AF: 0.148

Gnomad4 OTH AF: 0.108

Alfa AF: 0.108 Hom.: 357

Bravo AF: 0.115

TwinsUK AF: 0.153 AC: 568

ALSPAC AF: 0.140 AC: 539

ESP6500AA AF: 0.0372 AC: 164

ESP6500EA AF: 0.144 AC: 1242

ExAC AF: 0.159 AC: 19271

Asia WGS AF: 0.239 AC: 828 AN: 3478

EpiCase AF: 0.150

EpiControl AF: 0.146

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	This variant is associated with the following publications: (PMID: 25164601) -

Charcot-Marie-Tooth disease Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

Inherited Neuropathy Consortium

-

- -

Autosomal dominant slowed nerve conduction velocity Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 29, 2023

- -

ARHGEF10-related condition Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 18, 2019

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	0.14
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.38
Cadd	Benign	14
Dann	Uncertain	0.98
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.95
FATHMM_MKL	Benign	0.42	N
MetaRNN	Benign	0.0062	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.79	P;P;P;P;P;P
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.6	N;N;N;N;.;N
REVEL	Benign	0.23
Sift	Benign	0.20	T;T;T;T;.;T
Sift4G	Benign	0.19	T;T;T;T;T;T
Polyphen		0.71	P;D;.;D;.;.
Vest4		0.17
MutPred		0.42		.;.;Loss of stability (P = 0.1226);Loss of stability (P = 0.1226);.;.;
MPC		0.24
ClinPred		0.030	T
GERP RS		-4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.036
gMVP		0.24

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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

Other links and lift over

dbSNP: rs9657362; hg19: chr8-1833801; COSMIC: COSV50643418;