8-1906652-C-G

Variant names:

• chr8-1906652-C-G
• rs4376531
• NM_014629.4:c.1967+936C>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.1967+936C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.25 in 151,932 control chromosomes in the GnomAD database, including 5,489 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 (5489 hom., cov: 32)
• Consequence: ARHGEF10 NM_014629.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.791
• Publications: 14 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=-1.02).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.401 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGEF10	NM_014629.4	c.1967+936C>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.1967+936C>G		intron_variant	Intron 17 of 28	1	NM_014629.4	ENSP00000340297.3
KBTBD11-OT1	ENST00000635855.1	n.*1921+936C>G		intron_variant	Intron 18 of 29	5		ENSP00000489726.1

Frequencies

GnomAD3 genomes AF: 0.249 AC: 37852 AN: 151814 Hom.: 5458 Cov.: 32

Gnomad AFR AF: 0.405

Gnomad AMI AF: 0.283

Gnomad AMR AF: 0.166

Gnomad ASJ AF: 0.195

Gnomad EAS AF: 0.0949

Gnomad SAS AF: 0.139

Gnomad FIN AF: 0.165

Gnomad MID AF: 0.256

Gnomad NFE AF: 0.209

Gnomad OTH AF: 0.240

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

GnomAD4 genome AF: 0.250 AC: 37934 AN: 151932 Hom.: 5489 Cov.: 32 AF XY: 0.244 AC XY: 18105 AN XY: 74282

African (AFR) AF: 0.406 AC: 16782 AN: 41336

American (AMR) AF: 0.165 AC: 2528 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.195 AC: 676 AN: 3464

East Asian (EAS) AF: 0.0950 AC: 491 AN: 5170

South Asian (SAS) AF: 0.139 AC: 668 AN: 4820

European-Finnish (FIN) AF: 0.165 AC: 1749 AN: 10584

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

European-Non Finnish (NFE) AF: 0.209 AC: 14195 AN: 67958

Other (OTH) AF: 0.241 AC: 510 AN: 2116

Alfa AF: 0.107 Hom.: 164

Bravo AF: 0.257

Asia WGS AF: 0.137 AC: 476 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	0.26
DANN	Benign	0.56
PhyloP100		-0.79
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: rs4376531; hg19: chr8-1854818;