8-1940281-T-C

Variant names:

• chr8-1940281-T-C
• rs3824141
• NM_014629.4:c.3223-5200T>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.3223-5200T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.143 in 152,168 control chromosomes in the GnomAD database, including 1,839 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 0.14 (1839 hom., cov: 32)
• Consequence: ARHGEF10 NM_014629.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.931
• 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=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.315 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGEF10	NM_014629.4	MANE Select	c.3223-5200T>C		intron	N/A	NP_055444.2
	ARHGEF10	NM_001438091.1		c.3226-5200T>C		intron	N/A	NP_001425020.1
	ARHGEF10	NM_001308153.3		c.3223-5200T>C		intron	N/A	NP_001295082.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGEF10	ENST00000349830.8	TSL:1 MANE Select	c.3223-5200T>C		intron	N/A	ENSP00000340297.3
	ARHGEF10	ENST00000518288.5	TSL:1	c.3295-5200T>C		intron	N/A	ENSP00000431012.1
	ARHGEF10	ENST00000520359.5	TSL:1	c.3109-5200T>C		intron	N/A	ENSP00000427909.1

Frequencies

GnomAD3 genomes AF: 0.143 AC: 21770 AN: 152048 Hom.: 1830 Cov.: 32

Gnomad AFR AF: 0.178

Gnomad AMI AF: 0.0956

Gnomad AMR AF: 0.0819

Gnomad ASJ AF: 0.123

Gnomad EAS AF: 0.328

Gnomad SAS AF: 0.170

Gnomad FIN AF: 0.231

Gnomad MID AF: 0.155

Gnomad NFE AF: 0.107

Gnomad OTH AF: 0.149

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

GnomAD4 genome AF: 0.143 AC: 21794 AN: 152168 Hom.: 1839 Cov.: 32 AF XY: 0.149 AC XY: 11083 AN XY: 74404

African (AFR) AF: 0.178 AC: 7388 AN: 41490

American (AMR) AF: 0.0818 AC: 1252 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.123 AC: 426 AN: 3468

East Asian (EAS) AF: 0.328 AC: 1696 AN: 5170

South Asian (SAS) AF: 0.170 AC: 821 AN: 4828

European-Finnish (FIN) AF: 0.231 AC: 2445 AN: 10592

Middle Eastern (MID) AF: 0.150 AC: 44 AN: 294

European-Non Finnish (NFE) AF: 0.107 AC: 7305 AN: 68002

Other (OTH) AF: 0.156 AC: 330 AN: 2114

Alfa AF: 0.118 Hom.: 3719

Bravo AF: 0.136

Asia WGS AF: 0.273 AC: 948 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.50
DANN	Benign	0.53
PhyloP100		-0.93
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: rs3824141; hg19: chr8-1888447;