8-1876247-G-A

Variant names:

• chr8-1876247-G-A
• rs3735875
• ENST00000523711.5:n.197G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000523711.5(ARHGEF10):​n.197G>A variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.233 in 381,734 control chromosomes in the GnomAD database, including 11,419 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.24 (4665 hom., cov: 34)
  • Exomes 𝑓: 0.23 (6754 hom.)
• Consequence: ARHGEF10 ENST00000523711.5 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.29
• Publications: 3 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.345 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGEF10	NM_014629.4	c.680-324G>A		intron_variant	Intron 7 of 28	ENST00000349830.8	NP_055444.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARHGEF10	ENST00000349830.8	c.680-324G>A		intron_variant	Intron 7 of 28	1	NM_014629.4	ENSP00000340297.3
KBTBD11-OT1	ENST00000635855.1	n.*634-324G>A		intron_variant	Intron 8 of 29	5		ENSP00000489726.1

Frequencies

GnomAD3 genomes AF: 0.241 AC: 36585 AN: 152008 Hom.: 4645 Cov.: 34

Gnomad AFR AF: 0.205

Gnomad AMI AF: 0.216

Gnomad AMR AF: 0.336

Gnomad ASJ AF: 0.184

Gnomad EAS AF: 0.358

Gnomad SAS AF: 0.182

Gnomad FIN AF: 0.291

Gnomad MID AF: 0.130

Gnomad NFE AF: 0.232

Gnomad OTH AF: 0.229

GnomAD4 exome AF: 0.228 AC: 52450 AN: 229608 Hom.: 6754 Cov.: 0 AF XY: 0.222 AC XY: 26529 AN XY: 119762

African (AFR) AF: 0.193 AC: 1504 AN: 7796

American (AMR) AF: 0.392 AC: 3336 AN: 8520

Ashkenazi Jewish (ASJ) AF: 0.184 AC: 1326 AN: 7204

East Asian (EAS) AF: 0.343 AC: 4651 AN: 13568

South Asian (SAS) AF: 0.159 AC: 4404 AN: 27648

European-Finnish (FIN) AF: 0.289 AC: 3191 AN: 11032

Middle Eastern (MID) AF: 0.123 AC: 121 AN: 984

European-Non Finnish (NFE) AF: 0.222 AC: 31018 AN: 139434

Other (OTH) AF: 0.216 AC: 2899 AN: 13422

GnomAD4 genome AF: 0.241 AC: 36657 AN: 152126 Hom.: 4665 Cov.: 34 AF XY: 0.244 AC XY: 18122 AN XY: 74350

African (AFR) AF: 0.206 AC: 8553 AN: 41508

American (AMR) AF: 0.337 AC: 5149 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.184 AC: 638 AN: 3468

East Asian (EAS) AF: 0.359 AC: 1854 AN: 5170

South Asian (SAS) AF: 0.182 AC: 881 AN: 4830

European-Finnish (FIN) AF: 0.291 AC: 3071 AN: 10568

Middle Eastern (MID) AF: 0.133 AC: 39 AN: 294

European-Non Finnish (NFE) AF: 0.232 AC: 15786 AN: 67978

Other (OTH) AF: 0.232 AC: 489 AN: 2110

Alfa AF: 0.237 Hom.: 986

Bravo AF: 0.248

Asia WGS AF: 0.289 AC: 1004 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.063
DANN	Benign	0.67
PhyloP100		-1.3
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs3735875; hg19: chr8-1824413;