8-1951525-T-C

Variant names:

• chr8-1951525-T-C
• rs17830107
• NM_014629.4:c.3398-1180T>C

Variant summary

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

The NM_014629.4(ARHGEF10):​c.3398-1180T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.365 in 152,144 control chromosomes in the GnomAD database, including 10,418 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 0.36 (10418 hom., cov: 33)
• Consequence: ARHGEF10 NM_014629.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.429
• Publications: 6 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.544 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.3398-1180T>C		intron	N/A	NP_055444.2	O15013-5
	ARHGEF10	NM_001438091.1		c.3401-1180T>C		intron	N/A	NP_001425020.1
	ARHGEF10	NM_001308153.3		c.3398-1180T>C		intron	N/A	NP_001295082.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGEF10	ENST00000349830.8	TSL:1 MANE Select	c.3398-1180T>C		intron	N/A	ENSP00000340297.3	O15013-5
	ARHGEF10	ENST00000518288.5	TSL:1	c.3470-1180T>C		intron	N/A	ENSP00000431012.1	O15013-6
	ARHGEF10	ENST00000520359.5	TSL:1	c.3284-1180T>C		intron	N/A	ENSP00000427909.1	O15013-7

Frequencies

GnomAD3 genomes AF: 0.365 AC: 55462 AN: 152026 Hom.: 10416 Cov.: 33

Gnomad AFR AF: 0.325

Gnomad AMI AF: 0.340

Gnomad AMR AF: 0.288

Gnomad ASJ AF: 0.381

Gnomad EAS AF: 0.562

Gnomad SAS AF: 0.424

Gnomad FIN AF: 0.470

Gnomad MID AF: 0.386

Gnomad NFE AF: 0.370

Gnomad OTH AF: 0.375

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

GnomAD4 genome AF: 0.365 AC: 55478 AN: 152144 Hom.: 10418 Cov.: 33 AF XY: 0.370 AC XY: 27505 AN XY: 74382

African (AFR) AF: 0.325 AC: 13478 AN: 41484

American (AMR) AF: 0.288 AC: 4404 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.381 AC: 1319 AN: 3462

East Asian (EAS) AF: 0.561 AC: 2902 AN: 5172

South Asian (SAS) AF: 0.425 AC: 2049 AN: 4826

European-Finnish (FIN) AF: 0.470 AC: 4971 AN: 10572

Middle Eastern (MID) AF: 0.388 AC: 114 AN: 294

European-Non Finnish (NFE) AF: 0.369 AC: 25128 AN: 68006

Other (OTH) AF: 0.381 AC: 803 AN: 2108

Alfa AF: 0.356 Hom.: 16962

Bravo AF: 0.350

Asia WGS AF: 0.523 AC: 1820 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.87
DANN	Benign	0.75
PhyloP100		-0.43
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: rs17830107; hg19: chr8-1899691;