rs2272611

chr8-1928465-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_014629.4(ARHGEF10):c.2736C>T(p.Ile912=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.145 in 1,612,186 control chromosomes in the GnomAD database, including 17,512 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1566 hom., cov: 33)
  • Exomes 𝑓: 0.15 (15946 hom.)
• Consequence: ARHGEF10 NM_014629.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.317

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 8-1928465-C-T is Benign according to our data. Variant chr8-1928465-C-T is described in ClinVar as [Benign]. Clinvar id is 1282318.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-1928465-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.317 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.178 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARHGEF10	NM_014629.4	c.2736C>T	p.Ile912=	synonymous_variant	24/29	ENST00000349830.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARHGEF10	ENST00000349830.8	c.2736C>T	p.Ile912=	synonymous_variant	24/29	1	NM_014629.4	P4

Frequencies

GnomAD3 genomes AF: 0.143 AC: 21645 AN: 151838 Hom.: 1567 Cov.: 33

Gnomad AFR AF: 0.120

Gnomad AMI AF: 0.174

Gnomad AMR AF: 0.184

Gnomad ASJ AF: 0.151

Gnomad EAS AF: 0.175

Gnomad SAS AF: 0.135

Gnomad FIN AF: 0.182

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.139

Gnomad OTH AF: 0.133

GnomAD3 exomes AF: 0.161 AC: 40456 AN: 251480 Hom.: 3576 AF XY: 0.157 AC XY: 21385 AN XY: 135912

Gnomad AFR exome AF: 0.118

Gnomad AMR exome AF: 0.250

Gnomad ASJ exome AF: 0.149

Gnomad EAS exome AF: 0.168

Gnomad SAS exome AF: 0.140

Gnomad FIN exome AF: 0.179

Gnomad NFE exome AF: 0.142

Gnomad OTH exome AF: 0.156

GnomAD4 exome AF: 0.145 AC: 212286 AN: 1460230 Hom.: 15946 Cov.: 35 AF XY: 0.144 AC XY: 104807 AN XY: 726486

Gnomad4 AFR exome AF: 0.119

Gnomad4 AMR exome AF: 0.243

Gnomad4 ASJ exome AF: 0.148

Gnomad4 EAS exome AF: 0.181

Gnomad4 SAS exome AF: 0.138

Gnomad4 FIN exome AF: 0.177

Gnomad4 NFE exome AF: 0.140

Gnomad4 OTH exome AF: 0.139

GnomAD4 genome AF: 0.142 AC: 21647 AN: 151956 Hom.: 1566 Cov.: 33 AF XY: 0.145 AC XY: 10768 AN XY: 74280

Gnomad4 AFR AF: 0.120

Gnomad4 AMR AF: 0.184

Gnomad4 ASJ AF: 0.151

Gnomad4 EAS AF: 0.176

Gnomad4 SAS AF: 0.134

Gnomad4 FIN AF: 0.182

Gnomad4 NFE AF: 0.139

Gnomad4 OTH AF: 0.131

Alfa AF: 0.139 Hom.: 2767

Bravo AF: 0.145

Asia WGS AF: 0.152 AC: 529 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	- -
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

Mar 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
BayesDel_noAF	Benign	-0.54
Cadd	Benign	4.7
Dann	Benign	0.67

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs2272611; hg19: chr8-1876631; COSMIC: COSV50642448; COSMIC: COSV50642448;