8-1857879-GATCTATCTATCTATCTATCTATCTATCTATCT-GATCTATCTATCTATCT

Variant names:

• chr8-1857879-GATCTATCTATCTATCT-G
• rs35698984
• NM_014629.4:c.38-48_38-33delATCTATCTATCTATCT

Variant summary

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

The NM_014629.4(ARHGEF10):​c.38-48_38-33delATCTATCTATCTATCT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00347 in 594,344 control chromosomes in the GnomAD database, including 4 homozygotes. 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 0.0023 (0 hom., cov: 24)
  • Exomes 𝑓: 0.0038 (4 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 GnomAd4 at 257 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.38-48_38-33delATCTATCTATCTATCT		intron	N/A	NP_055444.2	O15013-5
	ARHGEF10	NM_001438091.1		c.38-48_38-33delATCTATCTATCTATCT		intron	N/A	NP_001425020.1
	ARHGEF10	NM_001308153.3		c.38-48_38-33delATCTATCTATCTATCT		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_38-65delATCTATCTATCTATCT		intron	N/A	ENSP00000340297.3	O15013-5
	ARHGEF10	ENST00000518288.5	TSL:1	c.110-80_110-65delATCTATCTATCTATCT		intron	N/A	ENSP00000431012.1	O15013-6
	ARHGEF10	ENST00000520359.5	TSL:1	c.38-80_38-65delATCTATCTATCTATCT		intron	N/A	ENSP00000427909.1	O15013-7

Frequencies

GnomAD3 genomes AF: 0.00226 AC: 257 AN: 113632 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.000957

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000442

Gnomad ASJ AF: 0.000371

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000552

Gnomad FIN AF: 0.00497

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00337

Gnomad OTH AF: 0.00129

GnomAD4 exome AF: 0.00376 AC: 1806 AN: 480640 Hom.: 4 AF XY: 0.00351 AC XY: 894 AN XY: 255056

African (AFR) AF: 0.00175 AC: 20 AN: 11426

American (AMR) AF: 0.000350 AC: 8 AN: 22832

Ashkenazi Jewish (ASJ) AF: 0.000507 AC: 7 AN: 13808

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

South Asian (SAS) AF: 0.000242 AC: 11 AN: 45536

European-Finnish (FIN) AF: 0.00318 AC: 109 AN: 34240

Middle Eastern (MID) AF: 0.000435 AC: 1 AN: 2300

European-Non Finnish (NFE) AF: 0.00533 AC: 1588 AN: 297920

Other (OTH) AF: 0.00248 AC: 62 AN: 24988

GnomAD4 genome AF: 0.00226 AC: 257 AN: 113704 Hom.: 0 Cov.: 24 AF XY: 0.00218 AC XY: 120 AN XY: 55142

African (AFR) AF: 0.000955 AC: 26 AN: 27228

American (AMR) AF: 0.000442 AC: 5 AN: 11318

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 4316

South Asian (SAS) AF: 0.000551 AC: 2 AN: 3630

European-Finnish (FIN) AF: 0.00497 AC: 37 AN: 7438

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 210

European-Non Finnish (NFE) AF: 0.00337 AC: 184 AN: 54642

Other (OTH) AF: 0.00128 AC: 2 AN: 1564

Alfa AF: 0.000527 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;