chr8-1857879-GATCTATCT-G

Variant names:

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

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_38-33delATCTATCT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00513 in 593,506 control chromosomes in the GnomAD database, including 18 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0080 (9 hom., cov: 24)
  • Exomes 𝑓: 0.0045 (9 hom.)
• Consequence: ARHGEF10 NM_014629.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.10
• 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 = 0.00796 (905/113692) while in subpopulation EAS AF = 0.0278 (120/4316). AF 95% confidence interval is 0.0238. There are 9 homozygotes in GnomAd4. There are 414 alleles in the male GnomAd4 subpopulation. Median coverage is 24. This position passed quality control check.
• BS2: High AC in GnomAd4 at 905 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_38-33delATCTATCT		intron	N/A	NP_055444.2	O15013-5
	ARHGEF10	NM_001438091.1		c.38-40_38-33delATCTATCT		intron	N/A	NP_001425020.1
	ARHGEF10	NM_001308153.3		c.38-40_38-33delATCTATCT		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.38-80_38-73delATCTATCT		intron	N/A	ENSP00000340297.3	O15013-5
	ARHGEF10	ENST00000518288.5	TSL:1	c.110-80_110-73delATCTATCT		intron	N/A	ENSP00000431012.1	O15013-6
	ARHGEF10	ENST00000520359.5	TSL:1	c.38-80_38-73delATCTATCT		intron	N/A	ENSP00000427909.1	O15013-7

Frequencies

GnomAD3 genomes AF: 0.00798 AC: 907 AN: 113620 Hom.: 9 Cov.: 24

Gnomad AFR AF: 0.0232

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00221

Gnomad ASJ AF: 0.000371

Gnomad EAS AF: 0.0280

Gnomad SAS AF: 0.00165

Gnomad FIN AF: 0.00309

Gnomad MID AF: 0.00450

Gnomad NFE AF: 0.00156

Gnomad OTH AF: 0.0103

GnomAD4 exome AF: 0.00446 AC: 2139 AN: 479814 Hom.: 9 AF XY: 0.00422 AC XY: 1074 AN XY: 254586

African (AFR) AF: 0.0240 AC: 274 AN: 11420

American (AMR) AF: 0.00167 AC: 38 AN: 22820

Ashkenazi Jewish (ASJ) AF: 0.00116 AC: 16 AN: 13770

East Asian (EAS) AF: 0.0334 AC: 920 AN: 27582

South Asian (SAS) AF: 0.00236 AC: 107 AN: 45424

European-Finnish (FIN) AF: 0.00386 AC: 132 AN: 34190

Middle Eastern (MID) AF: 0.00261 AC: 6 AN: 2296

European-Non Finnish (NFE) AF: 0.00183 AC: 545 AN: 297350

Other (OTH) AF: 0.00405 AC: 101 AN: 24962

GnomAD4 genome AF: 0.00796 AC: 905 AN: 113692 Hom.: 9 Cov.: 24 AF XY: 0.00751 AC XY: 414 AN XY: 55138

African (AFR) AF: 0.0231 AC: 629 AN: 27216

American (AMR) AF: 0.00221 AC: 25 AN: 11318

Ashkenazi Jewish (ASJ) AF: 0.000371 AC: 1 AN: 2696

East Asian (EAS) AF: 0.0278 AC: 120 AN: 4316

South Asian (SAS) AF: 0.00138 AC: 5 AN: 3630

European-Finnish (FIN) AF: 0.00309 AC: 23 AN: 7436

Middle Eastern (MID) AF: 0.00476 AC: 1 AN: 210

European-Non Finnish (NFE) AF: 0.00156 AC: 85 AN: 54644

Other (OTH) AF: 0.0102 AC: 16 AN: 1564

Alfa AF: 0.00 Hom.: 20

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.1
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;