8-1907598-C-G

Variant names:

• chr8-1907598-C-G
• rs2280887
• NM_014629.4:c.1968-1697C>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_014629.4(ARHGEF10):​c.1968-1697C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.251 in 152,090 control chromosomes in the GnomAD database, including 5,588 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.25 (5588 hom., cov: 33)
• Consequence: ARHGEF10 NM_014629.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.88
• Publications: 3 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: Unknown, AD Classification: SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.01).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.403 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGEF10	NM_014629.4	c.1968-1697C>G		intron_variant	Intron 17 of 28	ENST00000349830.8	NP_055444.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARHGEF10	ENST00000349830.8	c.1968-1697C>G		intron_variant	Intron 17 of 28	1	NM_014629.4	ENSP00000340297.3
KBTBD11-OT1	ENST00000635855.1	n.*1922-1697C>G		intron_variant	Intron 18 of 29	5		ENSP00000489726.1

Frequencies

GnomAD3 genomes AF: 0.250 AC: 38017 AN: 151972 Hom.: 5557 Cov.: 33

Gnomad AFR AF: 0.408

Gnomad AMI AF: 0.286

Gnomad AMR AF: 0.165

Gnomad ASJ AF: 0.205

Gnomad EAS AF: 0.0970

Gnomad SAS AF: 0.139

Gnomad FIN AF: 0.166

Gnomad MID AF: 0.256

Gnomad NFE AF: 0.208

Gnomad OTH AF: 0.239

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.251 AC: 38100 AN: 152090 Hom.: 5588 Cov.: 33 AF XY: 0.245 AC XY: 18192 AN XY: 74344

African (AFR) AF: 0.409 AC: 16935 AN: 41450

American (AMR) AF: 0.164 AC: 2511 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.205 AC: 710 AN: 3468

East Asian (EAS) AF: 0.0971 AC: 502 AN: 5172

South Asian (SAS) AF: 0.139 AC: 671 AN: 4828

European-Finnish (FIN) AF: 0.166 AC: 1762 AN: 10594

Middle Eastern (MID) AF: 0.265 AC: 78 AN: 294

European-Non Finnish (NFE) AF: 0.208 AC: 14164 AN: 67982

Other (OTH) AF: 0.239 AC: 506 AN: 2114

Alfa AF: 0.107 Hom.: 168

Bravo AF: 0.257

Asia WGS AF: 0.138 AC: 482 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.66
DANN	Benign	0.57
PhyloP100		-1.9
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: rs2280887; hg19: chr8-1855764;