8-1857875-G-GATCTATCTATCTATCTATCT

Variant names:

• chr8-1857875-G-GATCTATCTATCTATCTATCT
• rs35711467
• NM_014629.4:c.38-82_38-81insTATCTATCTATCTATCTATC

Variant summary

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

The NM_014629.4(ARHGEF10):​c.38-82_38-81insTATCTATCTATCTATCTATC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000142 in 918,536 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 INS_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 0.000047 (0 hom., cov: 21)
  • Exomes 𝑓: 0.0000099 (0 hom.)
• Consequence: ARHGEF10 NM_014629.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.310
• 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 GnomAd4 at 5 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.38-82_38-81insTATCTATCTATCTATCTATC		intron	N/A	NP_055444.2	O15013-5
	ARHGEF10	NM_001438091.1		c.38-82_38-81insTATCTATCTATCTATCTATC		intron	N/A	NP_001425020.1
	ARHGEF10	NM_001308153.3		c.38-82_38-81insTATCTATCTATCTATCTATC		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.38-85_38-84insATCTATCTATCTATCTATCT		intron	N/A	ENSP00000340297.3	O15013-5
	ARHGEF10	ENST00000518288.5	TSL:1	c.110-85_110-84insATCTATCTATCTATCTATCT		intron	N/A	ENSP00000431012.1	O15013-6
	ARHGEF10	ENST00000520359.5	TSL:1	c.38-85_38-84insATCTATCTATCTATCTATCT		intron	N/A	ENSP00000427909.1	O15013-7

Frequencies

GnomAD3 genomes AF: 0.0000373 AC: 4 AN: 107330 Hom.: 0 Cov.: 21

Gnomad AFR AF: 0.00

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: 0.000163

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000615

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000986 AC: 8 AN: 811118 Hom.: 0 AF XY: 0.0000120 AC XY: 5 AN XY: 418256

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

African (AFR) AF: 0.00 AC: 0 AN: 20208

American (AMR) AF: 0.00 AC: 0 AN: 32524

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20104

East Asian (EAS) AF: 0.00 AC: 0 AN: 32450

South Asian (SAS) AF: 0.0000163 AC: 1 AN: 61300

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45518

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3816

European-Non Finnish (NFE) AF: 0.0000126 AC: 7 AN: 557016

Other (OTH) AF: 0.00 AC: 0 AN: 38182

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000388203), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000465 AC: 5 AN: 107418 Hom.: 0 Cov.: 21 AF XY: 0.0000578 AC XY: 3 AN XY: 51924

African (AFR) AF: 0.0000324 AC: 1 AN: 30820

American (AMR) AF: 0.00 AC: 0 AN: 10232

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2290

East Asian (EAS) AF: 0.00 AC: 0 AN: 3490

South Asian (SAS) AF: 0.00 AC: 0 AN: 3406

European-Finnish (FIN) AF: 0.000163 AC: 1 AN: 6132

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 204

European-Non Finnish (NFE) AF: 0.0000615 AC: 3 AN: 48754

Other (OTH) AF: 0.00 AC: 0 AN: 1484

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.31

Splicing

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

Other links and lift over

dbSNP: rs35711467; hg19: chr8-1806041;