8-1857879-GATCTATCTATCTATCTATCTATCTATCTATCT-GATCTATCTATCT

Variant names:

• chr8-1857879-GATCTATCTATCTATCTATCT-G
• rs35698984
• NM_014629.4:c.38-52_38-33delATCTATCTATCTATCTATCT

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_014629.4(ARHGEF10):​c.38-52_38-33delATCTATCTATCTATCTATCT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000135 in 594,300 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0000088 (0 hom., cov: 24)
  • Exomes 𝑓: 0.000015 (0 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: Likely_benign. The variant received -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 7 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.38-52_38-33delATCTATCTATCTATCTATCT		intron	N/A	NP_055444.2	O15013-5
	ARHGEF10	NM_001438091.1		c.38-52_38-33delATCTATCTATCTATCTATCT		intron	N/A	NP_001425020.1
	ARHGEF10	NM_001308153.3		c.38-52_38-33delATCTATCTATCTATCTATCT		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_38-61delATCTATCTATCTATCTATCT		intron	N/A	ENSP00000340297.3	O15013-5
	ARHGEF10	ENST00000518288.5	TSL:1	c.110-80_110-61delATCTATCTATCTATCTATCT		intron	N/A	ENSP00000431012.1	O15013-6
	ARHGEF10	ENST00000520359.5	TSL:1	c.38-80_38-61delATCTATCTATCTATCTATCT		intron	N/A	ENSP00000427909.1	O15013-7

Frequencies

GnomAD3 genomes AF: 0.00000880 AC: 1 AN: 113632 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.0000368

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000146 AC: 7 AN: 480668 Hom.: 0 AF XY: 0.0000196 AC XY: 5 AN XY: 255066

African (AFR) AF: 0.0000875 AC: 1 AN: 11426

American (AMR) AF: 0.00 AC: 0 AN: 22832

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13808

East Asian (EAS) AF: 0.00 AC: 0 AN: 27590

South Asian (SAS) AF: 0.00 AC: 0 AN: 45536

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34238

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2300

European-Non Finnish (NFE) AF: 0.0000168 AC: 5 AN: 297950

Other (OTH) AF: 0.0000400 AC: 1 AN: 24988

GnomAD4 genome AF: 0.00000880 AC: 1 AN: 113632 Hom.: 0 Cov.: 24 AF XY: 0.0000182 AC XY: 1 AN XY: 55058

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000368 AC: 1 AN: 27156

American (AMR) AF: 0.00 AC: 0 AN: 11306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2696

East Asian (EAS) AF: 0.00 AC: 0 AN: 4326

South Asian (SAS) AF: 0.00 AC: 0 AN: 3626

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7438

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 222

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 54648

Other (OTH) AF: 0.00 AC: 0 AN: 1552

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.1

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;