rs2294039

Positions:

• chr8-1909425-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_014629.4(ARHGEF10):​c.2098G>A​(p.Val700Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0376 in 1,614,074 control chromosomes in the GnomAD database, including 1,272 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.031 (77 hom., cov: 33)
  • Exomes 𝑓: 0.038 (1195 hom.)
• Consequence: ARHGEF10 NM_014629.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.876

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=0.0030667782).
• BP6: Variant 8-1909425-G-A is Benign according to our data. Variant chr8-1909425-G-A is described in ClinVar as [Benign]. Clinvar id is 439414.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-1909425-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0306 (4668/152316) while in subpopulation NFE AF= 0.0402 (2735/68032). AF 95% confidence interval is 0.0389. There are 77 homozygotes in gnomad4. There are 2298 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 4668 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARHGEF10	NM_014629.4	c.2098G>A	p.Val700Ile	missense_variant	18/29	ENST00000349830.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARHGEF10	ENST00000349830.8	c.2098G>A	p.Val700Ile	missense_variant	18/29	1	NM_014629.4	P4

Frequencies

GnomAD3 genomes AF: 0.0306 AC: 4663 AN: 152198 Hom.: 77 Cov.: 33

Gnomad AFR AF: 0.0172

Gnomad AMI AF: 0.0252

Gnomad AMR AF: 0.0260

Gnomad ASJ AF: 0.0121

Gnomad EAS AF: 0.0193

Gnomad SAS AF: 0.0278

Gnomad FIN AF: 0.0435

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0402

Gnomad OTH AF: 0.0244

GnomAD3 exomes AF: 0.0315 AC: 7915 AN: 251342 Hom.: 152 AF XY: 0.0324 AC XY: 4403 AN XY: 135904

Gnomad AFR exome AF: 0.0148

Gnomad AMR exome AF: 0.0176

Gnomad ASJ exome AF: 0.0147

Gnomad EAS exome AF: 0.0193

Gnomad SAS exome AF: 0.0279

Gnomad FIN exome AF: 0.0433

Gnomad NFE exome AF: 0.0404

Gnomad OTH exome AF: 0.0287

GnomAD4 exome AF: 0.0383 AC: 56039 AN: 1461758 Hom.: 1195 Cov.: 65 AF XY: 0.0382 AC XY: 27775 AN XY: 727190

Gnomad4 AFR exome AF: 0.0155

Gnomad4 AMR exome AF: 0.0191

Gnomad4 ASJ exome AF: 0.0142

Gnomad4 EAS exome AF: 0.0221

Gnomad4 SAS exome AF: 0.0288

Gnomad4 FIN exome AF: 0.0427

Gnomad4 NFE exome AF: 0.0419

Gnomad4 OTH exome AF: 0.0333

GnomAD4 genome AF: 0.0306 AC: 4668 AN: 152316 Hom.: 77 Cov.: 33 AF XY: 0.0309 AC XY: 2298 AN XY: 74478

Gnomad4 AFR AF: 0.0173

Gnomad4 AMR AF: 0.0260

Gnomad4 ASJ AF: 0.0121

Gnomad4 EAS AF: 0.0193

Gnomad4 SAS AF: 0.0278

Gnomad4 FIN AF: 0.0435

Gnomad4 NFE AF: 0.0402

Gnomad4 OTH AF: 0.0242

Alfa AF: 0.0355 Hom.: 124

Bravo AF: 0.0281

TwinsUK AF: 0.0461 AC: 171

ALSPAC AF: 0.0394 AC: 152

ESP6500AA AF: 0.0159 AC: 70

ESP6500EA AF: 0.0401 AC: 345

ExAC AF: 0.0324 AC: 3938

Asia WGS AF: 0.0210 AC: 74 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal dominant slowed nerve conduction velocity Benign:3

Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Jan 15, 2015	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Clinical Genetics, Academic Medical Center

-

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

ARHGEF10-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 05, 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	0.073
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	5.4
DANN	Benign	0.85
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.11	N
MetaRNN	Benign	0.0031	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.25	N;N;N;N;N
REVEL	Benign	0.067
Sift	Benign	0.41	T;T;T;T;T
Sift4G	Benign	0.63	T;T;T;T;T
Polyphen		0.0050	B;B;.;B;.
Vest4		0.056
MPC		0.030
ClinPred		0.0022	T
GERP RS		2.0
Varity_R		0.014
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

Other links and lift over

dbSNP: rs2294039; hg19: chr8-1857591; COSMIC: COSV50643436;