8-1857879-GATCTATCTATCTATCTATCTATCTATCTATCT-GATCTATCTATCTATCTATCTATCTATCTATCTATCTATCT

Variant names:

• chr8-1857879-G-GATCTATCT
• rs35698984
• NM_014629.4:c.38-40_38-33dupATCTATCT

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The NM_014629.4(ARHGEF10):​c.38-40_38-33dupATCTATCT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0139 in 113,670 control chromosomes in the GnomAD database, including 12 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.014 (12 hom., cov: 24)
  • Exomes 𝑓: 0.013 (52 hom.)
  • Failed GnomAD Quality Control
• Consequence: ARHGEF10 NM_014629.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.397
• Publications: 1 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 -8 ACMG points.

• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0139 (1576/113670) while in subpopulation EAS AF = 0.0455 (196/4310). AF 95% confidence interval is 0.0403. There are 12 homozygotes in GnomAd4. There are 759 alleles in the male GnomAd4 subpopulation. Median coverage is 24. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1576 Unknown,AD gene.

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.38-40_38-33dupATCTATCT		intron	N/A	NP_055444.2	O15013-5
	ARHGEF10	NM_001438091.1		c.38-40_38-33dupATCTATCT		intron	N/A	NP_001425020.1
	ARHGEF10	NM_001308153.3		c.38-40_38-33dupATCTATCT		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.38-81_38-80insATCTATCT		intron	N/A	ENSP00000340297.3	O15013-5
	ARHGEF10	ENST00000518288.5	TSL:1	c.110-81_110-80insATCTATCT		intron	N/A	ENSP00000431012.1	O15013-6
	ARHGEF10	ENST00000520359.5	TSL:1	c.38-81_38-80insATCTATCT		intron	N/A	ENSP00000427909.1	O15013-7

Frequencies

GnomAD3 genomes AF: 0.0139 AC: 1576 AN: 113598 Hom.: 12 Cov.: 24

Gnomad AFR AF: 0.0142

Gnomad AMI AF: 0.0166

Gnomad AMR AF: 0.0103

Gnomad ASJ AF: 0.0282

Gnomad EAS AF: 0.0454

Gnomad SAS AF: 0.00966

Gnomad FIN AF: 0.00605

Gnomad MID AF: 0.0495

Gnomad NFE AF: 0.0124

Gnomad OTH AF: 0.0155

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0133 AC: 6384 AN: 480390 Hom.: 52 AF XY: 0.0135 AC XY: 3446 AN XY: 254902

African (AFR) AF: 0.0118 AC: 135 AN: 11422

American (AMR) AF: 0.00771 AC: 176 AN: 22820

Ashkenazi Jewish (ASJ) AF: 0.0233 AC: 321 AN: 13794

East Asian (EAS) AF: 0.0412 AC: 1136 AN: 27544

South Asian (SAS) AF: 0.0114 AC: 521 AN: 45516

European-Finnish (FIN) AF: 0.00578 AC: 198 AN: 34232

Middle Eastern (MID) AF: 0.0213 AC: 49 AN: 2296

European-Non Finnish (NFE) AF: 0.0117 AC: 3499 AN: 297802

Other (OTH) AF: 0.0140 AC: 349 AN: 24964

GnomAD4 genome AF: 0.0139 AC: 1576 AN: 113670 Hom.: 12 Cov.: 24 AF XY: 0.0138 AC XY: 759 AN XY: 55130

African (AFR) AF: 0.0142 AC: 386 AN: 27214

American (AMR) AF: 0.0103 AC: 116 AN: 11316

Ashkenazi Jewish (ASJ) AF: 0.0282 AC: 76 AN: 2696

East Asian (EAS) AF: 0.0455 AC: 196 AN: 4310

South Asian (SAS) AF: 0.00937 AC: 34 AN: 3628

European-Finnish (FIN) AF: 0.00605 AC: 45 AN: 7438

Middle Eastern (MID) AF: 0.0524 AC: 11 AN: 210

European-Non Finnish (NFE) AF: 0.0124 AC: 677 AN: 54634

Other (OTH) AF: 0.0154 AC: 24 AN: 1562

Alfa AF: 0.00181 Hom.: 20

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.40
Mutation Taster		=100/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs35698984; hg19: chr8-1806045;