8-1857875-G-GATCTATCTATCT

Variant names:

• chr8-1857875-G-GATCTATCTATCT
• rs35711467
• NM_014629.4:c.38-82_38-81insTATCTATCTATC

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_38-81insTATCTATCTATC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00371 in 918,338 control chromosomes in the GnomAD database, including 13 homozygotes. 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 0.0065 (6 hom., cov: 21)
  • Exomes 𝑓: 0.0033 (7 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: AD, Unknown Classification: SUPPORTIVE, LIMITED Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), 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 695 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_38-81insTATCTATCTATC		intron	N/A	NP_055444.2	O15013-5
	ARHGEF10	NM_001438091.1		c.38-82_38-81insTATCTATCTATC		intron	N/A	NP_001425020.1
	ARHGEF10	NM_001308153.3		c.38-82_38-81insTATCTATCTATC		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_38-84insATCTATCTATCT		intron	N/A	ENSP00000340297.3	O15013-5
	ARHGEF10	ENST00000518288.5	TSL:1	c.110-85_110-84insATCTATCTATCT		intron	N/A	ENSP00000431012.1	O15013-6
	ARHGEF10	ENST00000520359.5	TSL:1	c.38-85_38-84insATCTATCTATCT		intron	N/A	ENSP00000427909.1	O15013-7

Frequencies

GnomAD3 genomes AF: 0.00646 AC: 693 AN: 107316 Hom.: 6 Cov.: 21

Gnomad AFR AF: 0.00316

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00450

Gnomad ASJ AF: 0.00349

Gnomad EAS AF: 0.00944

Gnomad SAS AF: 0.00676

Gnomad FIN AF: 0.0140

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00814

Gnomad OTH AF: 0.00204

GnomAD4 exome AF: 0.00334 AC: 2711 AN: 810934 Hom.: 7 AF XY: 0.00339 AC XY: 1418 AN XY: 418166

African (AFR) AF: 0.00198 AC: 40 AN: 20202

American (AMR) AF: 0.00200 AC: 65 AN: 32508

Ashkenazi Jewish (ASJ) AF: 0.00134 AC: 27 AN: 20092

East Asian (EAS) AF: 0.00623 AC: 202 AN: 32440

South Asian (SAS) AF: 0.00357 AC: 219 AN: 61290

European-Finnish (FIN) AF: 0.00886 AC: 403 AN: 45484

Middle Eastern (MID) AF: 0.000787 AC: 3 AN: 3814

European-Non Finnish (NFE) AF: 0.00289 AC: 1612 AN: 556930

Other (OTH) AF: 0.00367 AC: 140 AN: 38174

GnomAD4 genome AF: 0.00647 AC: 695 AN: 107404 Hom.: 6 Cov.: 21 AF XY: 0.00653 AC XY: 339 AN XY: 51920

African (AFR) AF: 0.00318 AC: 98 AN: 30816

American (AMR) AF: 0.00450 AC: 46 AN: 10232

Ashkenazi Jewish (ASJ) AF: 0.00349 AC: 8 AN: 2290

East Asian (EAS) AF: 0.00946 AC: 33 AN: 3488

South Asian (SAS) AF: 0.00705 AC: 24 AN: 3406

European-Finnish (FIN) AF: 0.0140 AC: 86 AN: 6130

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

European-Non Finnish (NFE) AF: 0.00814 AC: 397 AN: 48748

Other (OTH) AF: 0.00202 AC: 3 AN: 1484

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.31
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: rs35711467; hg19: chr8-1806041;