8-1942367-T-C

Variant names:

• chr8-1942367-T-C
• rs7386016
• NM_014629.4:c.3223-3114T>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.3223-3114T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.897 in 151,438 control chromosomes in the GnomAD database, including 61,084 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 0.90 (61084 hom., cov: 27)
• Consequence: ARHGEF10 NM_014629.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.615
• 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: 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=-0.95).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.975 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.3223-3114T>C		intron	N/A	NP_055444.2	O15013-5
	ARHGEF10	NM_001438091.1		c.3226-3114T>C		intron	N/A	NP_001425020.1
	ARHGEF10	NM_001308153.3		c.3223-3114T>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.3223-3114T>C		intron	N/A	ENSP00000340297.3	O15013-5
	ARHGEF10	ENST00000518288.5	TSL:1	c.3295-3114T>C		intron	N/A	ENSP00000431012.1	O15013-6
	ARHGEF10	ENST00000520359.5	TSL:1	c.3109-3114T>C		intron	N/A	ENSP00000427909.1	O15013-7

Frequencies

GnomAD3 genomes AF: 0.897 AC: 135732 AN: 151320 Hom.: 61041 Cov.: 27

Gnomad AFR AF: 0.813

Gnomad AMI AF: 0.987

Gnomad AMR AF: 0.920

Gnomad ASJ AF: 0.910

Gnomad EAS AF: 0.998

Gnomad SAS AF: 0.960

Gnomad FIN AF: 0.954

Gnomad MID AF: 0.889

Gnomad NFE AF: 0.920

Gnomad OTH AF: 0.892

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

GnomAD4 genome AF: 0.897 AC: 135834 AN: 151438 Hom.: 61084 Cov.: 27 AF XY: 0.901 AC XY: 66609 AN XY: 73918

African (AFR) AF: 0.813 AC: 33469 AN: 41152

American (AMR) AF: 0.921 AC: 14011 AN: 15220

Ashkenazi Jewish (ASJ) AF: 0.910 AC: 3151 AN: 3464

East Asian (EAS) AF: 0.998 AC: 5134 AN: 5144

South Asian (SAS) AF: 0.960 AC: 4536 AN: 4726

European-Finnish (FIN) AF: 0.954 AC: 10021 AN: 10506

Middle Eastern (MID) AF: 0.884 AC: 258 AN: 292

European-Non Finnish (NFE) AF: 0.920 AC: 62489 AN: 67934

Other (OTH) AF: 0.893 AC: 1867 AN: 2090

Alfa AF: 0.912 Hom.: 101896

Bravo AF: 0.892

Asia WGS AF: 0.960 AC: 3336 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.63
DANN	Benign	0.66
PhyloP100		-0.61
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: rs7386016; hg19: chr8-1890533;