8-1901109-G-A

Variant names:

• chr8-1901109-G-A
• rs3758014
• NM_014629.4:c.1651-2172G>A

Variant summary

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

The NM_014629.4(ARHGEF10):​c.1651-2172G>A 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 151,982 control chromosomes in the GnomAD database, including 4,914 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 (4914 hom., cov: 30)
• Consequence: ARHGEF10 NM_014629.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.10
• Publications: 2 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=-0.95).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.319 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGEF10	NM_014629.4	c.1651-2172G>A		intron_variant	Intron 15 of 28	ENST00000349830.8	NP_055444.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARHGEF10	ENST00000349830.8	c.1651-2172G>A		intron_variant	Intron 15 of 28	1	NM_014629.4	ENSP00000340297.3
KBTBD11-OT1	ENST00000635855.1	n.*1605-2172G>A		intron_variant	Intron 16 of 29	5		ENSP00000489726.1

Frequencies

GnomAD3 genomes AF: 0.250 AC: 37932 AN: 151866 Hom.: 4908 Cov.: 30

Gnomad AFR AF: 0.234

Gnomad AMI AF: 0.0844

Gnomad AMR AF: 0.327

Gnomad ASJ AF: 0.317

Gnomad EAS AF: 0.117

Gnomad SAS AF: 0.256

Gnomad FIN AF: 0.219

Gnomad MID AF: 0.256

Gnomad NFE AF: 0.255

Gnomad OTH AF: 0.255

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

GnomAD4 genome AF: 0.250 AC: 37969 AN: 151982 Hom.: 4914 Cov.: 30 AF XY: 0.250 AC XY: 18542 AN XY: 74304

African (AFR) AF: 0.234 AC: 9681 AN: 41418

American (AMR) AF: 0.327 AC: 4992 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.317 AC: 1097 AN: 3460

East Asian (EAS) AF: 0.118 AC: 608 AN: 5170

South Asian (SAS) AF: 0.255 AC: 1226 AN: 4806

European-Finnish (FIN) AF: 0.219 AC: 2321 AN: 10578

Middle Eastern (MID) AF: 0.243 AC: 71 AN: 292

European-Non Finnish (NFE) AF: 0.255 AC: 17358 AN: 67968

Other (OTH) AF: 0.255 AC: 538 AN: 2112

Alfa AF: 0.263 Hom.: 8961

Bravo AF: 0.257

Asia WGS AF: 0.199 AC: 695 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.16
DANN	Benign	0.26
PhyloP100		-2.1
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: rs3758014; hg19: chr8-1849275;