rs999545

Variant names:

• chr8-1944676-A-G
• rs999545
• NM_014629.4:c.3223-805A>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.3223-805A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.324 in 151,982 control chromosomes in the GnomAD database, including 8,481 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 0.32 (8481 hom., cov: 34)
• Consequence: ARHGEF10 NM_014629.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0250
• Publications: 5 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=-0.99).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.402 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGEF10	NM_014629.4	c.3223-805A>G		intron_variant	Intron 26 of 28	ENST00000349830.8	NP_055444.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARHGEF10	ENST00000349830.8	c.3223-805A>G		intron_variant	Intron 26 of 28	1	NM_014629.4	ENSP00000340297.3
KBTBD11-OT1	ENST00000635855.1	n.*3177-805A>G		intron_variant	Intron 27 of 29	5		ENSP00000489726.1

Frequencies

GnomAD3 genomes AF: 0.324 AC: 49228 AN: 151864 Hom.: 8475 Cov.: 34

Gnomad AFR AF: 0.225

Gnomad AMI AF: 0.398

Gnomad AMR AF: 0.410

Gnomad ASJ AF: 0.384

Gnomad EAS AF: 0.186

Gnomad SAS AF: 0.357

Gnomad FIN AF: 0.337

Gnomad MID AF: 0.301

Gnomad NFE AF: 0.368

Gnomad OTH AF: 0.312

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

GnomAD4 genome AF: 0.324 AC: 49258 AN: 151982 Hom.: 8481 Cov.: 34 AF XY: 0.325 AC XY: 24138 AN XY: 74266

African (AFR) AF: 0.225 AC: 9307 AN: 41456

American (AMR) AF: 0.411 AC: 6278 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.384 AC: 1334 AN: 3470

East Asian (EAS) AF: 0.186 AC: 958 AN: 5156

South Asian (SAS) AF: 0.358 AC: 1722 AN: 4814

European-Finnish (FIN) AF: 0.337 AC: 3554 AN: 10550

Middle Eastern (MID) AF: 0.306 AC: 90 AN: 294

European-Non Finnish (NFE) AF: 0.368 AC: 24999 AN: 67930

Other (OTH) AF: 0.310 AC: 654 AN: 2112

Alfa AF: 0.361 Hom.: 6414

Bravo AF: 0.321

Asia WGS AF: 0.235 AC: 816 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	1.2
DANN	Benign	0.45
PhyloP100		-0.025
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: rs999545; hg19: chr8-1892842;