NM_014629.4:c.1110G>C

Variant names:

• chr8-1885635-G-C
• rs9657362
• NM_014629.4:c.1110G>C

Variant summary

Our verdict is Benign. The variant received -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. 14/21 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:5
• Conservation: PhyloP100: 0.730
• Publications: 29 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=0.0061654747).
• BP6: Variant 8-1885635-G-C is Benign according to our data. Variant chr8-1885635-G-C is described in ClinVar as Benign. ClinVar VariationId is 618536.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.272 is higher than 0.05.

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.1110G>C	p.Leu370Phe	missense	Exon 11 of 29	NP_055444.2	O15013-5
	ARHGEF10	NM_001438091.1		c.1113G>C	p.Leu371Phe	missense	Exon 11 of 29	NP_001425020.1
	ARHGEF10	NM_001308153.3		c.1113G>C	p.Leu371Phe	missense	Exon 12 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.1110G>C	p.Leu370Phe	missense	Exon 11 of 29	ENSP00000340297.3	O15013-5
	ARHGEF10	ENST00000518288.5	TSL:1	c.1185G>C	p.Leu395Phe	missense	Exon 12 of 30	ENSP00000431012.1	O15013-6
	ARHGEF10	ENST00000520359.5	TSL:1	c.996G>C	p.Leu332Phe	missense	Exon 10 of 28	ENSP00000427909.1	O15013-7

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

GnomAD2 exomes AF: 0.159 AC: 40013 AN: 251278 AF XY: 0.167

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 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

African (AFR) AF: 0.0280 AC: 938 AN: 33466

American (AMR) AF: 0.142 AC: 6341 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0788 AC: 2060 AN: 26130

East Asian (EAS) AF: 0.286 AC: 11349 AN: 39692

South Asian (SAS) AF: 0.276 AC: 23821 AN: 86218

European-Finnish (FIN) AF: 0.121 AC: 6427 AN: 53294

Middle Eastern (MID) AF: 0.137 AC: 793 AN: 5768

European-Non Finnish (NFE) AF: 0.152 AC: 169304 AN: 1111106

Other (OTH) AF: 0.156 AC: 9432 AN: 60342

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

African (AFR) AF: 0.0323 AC: 1339 AN: 41486

American (AMR) AF: 0.143 AC: 2187 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0789 AC: 274 AN: 3472

East Asian (EAS) AF: 0.284 AC: 1469 AN: 5168

South Asian (SAS) AF: 0.278 AC: 1335 AN: 4806

European-Finnish (FIN) AF: 0.106 AC: 1117 AN: 10544

Middle Eastern (MID) AF: 0.167 AC: 49 AN: 294

European-Non Finnish (NFE) AF: 0.148 AC: 10082 AN: 67970

Other (OTH) AF: 0.108 AC: 228 AN: 2114

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	ARHGEF10-related disorder (1)
-	-	1	Autosomal dominant slowed nerve conduction velocity (1)
-	1	-	Charcot-Marie-Tooth disease (1)

Computational scores

Source: dbNSFP v4.9

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
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.95
FATHMM_MKL	Benign	0.42	N
MetaRNN	Benign	0.0062	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		0.73
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.23
Sift	Benign	0.20	T
Sift4G	Benign	0.19	T
Polyphen		0.71	P
Vest4		0.17
MutPred		0.42		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
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

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