8-1909127-A-G

Variant names:

• chr8-1909127-A-G
• rs2294035
• NM_014629.4:c.1968-168A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_014629.4(ARHGEF10):​c.1968-168A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.577 in 152,092 control chromosomes in the GnomAD database, including 25,707 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.58 (25707 hom., cov: 33)
• Consequence: ARHGEF10 NM_014629.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.44
• Publications: 4 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 8-1909127-A-G is Benign according to our data. Variant chr8-1909127-A-G is described in ClinVar as Benign. ClinVar VariationId is 1262906.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.642 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.1968-168A>G		intron	N/A	NP_055444.2
	ARHGEF10	NM_001438091.1		c.1971-168A>G		intron	N/A	NP_001425020.1
	ARHGEF10	NM_001308153.3		c.1968-168A>G		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.1968-168A>G		intron	N/A	ENSP00000340297.3
	ARHGEF10	ENST00000518288.5	TSL:1	c.2040-168A>G		intron	N/A	ENSP00000431012.1
	ARHGEF10	ENST00000520359.5	TSL:1	c.1854-168A>G		intron	N/A	ENSP00000427909.1

Frequencies

GnomAD3 genomes AF: 0.577 AC: 87691 AN: 151974 Hom.: 25684 Cov.: 33

Gnomad AFR AF: 0.648

Gnomad AMI AF: 0.529

Gnomad AMR AF: 0.551

Gnomad ASJ AF: 0.540

Gnomad EAS AF: 0.582

Gnomad SAS AF: 0.548

Gnomad FIN AF: 0.616

Gnomad MID AF: 0.617

Gnomad NFE AF: 0.538

Gnomad OTH AF: 0.556

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

GnomAD4 genome AF: 0.577 AC: 87771 AN: 152092 Hom.: 25707 Cov.: 33 AF XY: 0.582 AC XY: 43242 AN XY: 74340

African (AFR) AF: 0.648 AC: 26914 AN: 41512

American (AMR) AF: 0.551 AC: 8422 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.540 AC: 1869 AN: 3464

East Asian (EAS) AF: 0.582 AC: 3018 AN: 5182

South Asian (SAS) AF: 0.547 AC: 2642 AN: 4826

European-Finnish (FIN) AF: 0.616 AC: 6500 AN: 10558

Middle Eastern (MID) AF: 0.616 AC: 181 AN: 294

European-Non Finnish (NFE) AF: 0.538 AC: 36570 AN: 67964

Other (OTH) AF: 0.558 AC: 1173 AN: 2102

Alfa AF: 0.542 Hom.: 85455

Bravo AF: 0.571

Asia WGS AF: 0.551 AC: 1917 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.085
DANN	Benign	0.25
PhyloP100		-1.4
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2294035; hg19: chr8-1857293;