rs2294039

Variant names:

• chr8-1909425-G-A
• rs2294039
• NM_014629.4:c.2098G>A

Variant summary

Our verdict is Benign. The variant received -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. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• 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:7
• Conservation: PhyloP100: 0.876
• Publications: 20 publications found

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: AD, Unknown Classification: SUPPORTIVE, LIMITED Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Orphanet
• hereditary peripheral neuropathy

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• peripheral neuropathy

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

KBTBD11-OT1 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 439414.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 4668 AD,Unknown gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014629.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGEF10	NM_014629.4	MANE Select	c.2098G>A	p.Val700Ile	missense	Exon 18 of 29	NP_055444.2	O15013-5
	ARHGEF10	NM_001438091.1		c.2101G>A	p.Val701Ile	missense	Exon 18 of 29	NP_001425020.1
	ARHGEF10	NM_001308153.3		c.2098G>A	p.Val700Ile	missense	Exon 19 of 30	NP_001295082.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGEF10	ENST00000349830.8	TSL:1 MANE Select	c.2098G>A	p.Val700Ile	missense	Exon 18 of 29	ENSP00000340297.3	O15013-5
	ARHGEF10	ENST00000518288.5	TSL:1	c.2170G>A	p.Val724Ile	missense	Exon 19 of 30	ENSP00000431012.1	O15013-6
	ARHGEF10	ENST00000520359.5	TSL:1	c.1984G>A	p.Val662Ile	missense	Exon 17 of 28	ENSP00000427909.1	O15013-7

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

GnomAD2 exomes AF: 0.0315 AC: 7915 AN: 251342 AF XY: 0.0324

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 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

African (AFR) AF: 0.0155 AC: 519 AN: 33480

American (AMR) AF: 0.0191 AC: 852 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0142 AC: 372 AN: 26134

East Asian (EAS) AF: 0.0221 AC: 879 AN: 39700

South Asian (SAS) AF: 0.0288 AC: 2484 AN: 86258

European-Finnish (FIN) AF: 0.0427 AC: 2274 AN: 53296

Middle Eastern (MID) AF: 0.00745 AC: 43 AN: 5768

European-Non Finnish (NFE) AF: 0.0419 AC: 46604 AN: 1112006

Other (OTH) AF: 0.0333 AC: 2012 AN: 60394

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

African (AFR) AF: 0.0173 AC: 719 AN: 41584

American (AMR) AF: 0.0260 AC: 398 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0121 AC: 42 AN: 3470

East Asian (EAS) AF: 0.0193 AC: 100 AN: 5176

South Asian (SAS) AF: 0.0278 AC: 134 AN: 4818

European-Finnish (FIN) AF: 0.0435 AC: 462 AN: 10620

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0402 AC: 2735 AN: 68032

Other (OTH) AF: 0.0242 AC: 51 AN: 2110

Alfa AF: 0.0346 Hom.: 160

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Autosomal dominant slowed nerve conduction velocity (3)
-	-	2	not provided (2)
-	-	1	ARHGEF10-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
DEOGEN2	Benign	0.013	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.11	N
MetaRNN	Benign	0.0031	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L
PhyloP100		0.88
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.25	N
REVEL	Benign	0.067
Sift	Benign	0.41	T
Sift4G	Benign	0.63	T
Polyphen		0.0050	B
Vest4		0.056
MPC		0.030
ClinPred		0.0022	T
GERP RS		2.0
Varity_R		0.014
gMVP		0.17
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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