8-1957657-A-G

Variant names:

• chr8-1957657-A-G
• rs6991392
• ENST00000635855.1:n.*4383A>G

Variant summary

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

The ENST00000635855.1(KBTBD11-OT1):​n.*4383A>G 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 0.378 in 197,908 control chromosomes in the GnomAD database, including 14,149 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 0.37 (10642 hom., cov: 34)
  • Exomes 𝑓: 0.40 (3507 hom.)
• Consequence: KBTBD11-OT1 ENST00000635855.1 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.21
• Publications: 12 publications found

Genes affected

KBTBD11-OT1 (HGNC:):

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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.557 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000635855.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGEF10	NM_014629.4	MANE Select	c.*394A>G		3_prime_UTR	Exon 29 of 29	NP_055444.2
	ARHGEF10	NM_001438091.1		c.*394A>G		3_prime_UTR	Exon 29 of 29	NP_001425020.1
	ARHGEF10	NM_001308153.3		c.*394A>G		3_prime_UTR	Exon 30 of 30	NP_001295082.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KBTBD11-OT1	ENST00000635855.1	TSL:5	n.*4383A>G		non_coding_transcript_exon	Exon 30 of 30	ENSP00000489726.1
	ARHGEF10	ENST00000349830.8	TSL:1 MANE Select	c.*394A>G		3_prime_UTR	Exon 29 of 29	ENSP00000340297.3
	ARHGEF10	ENST00000518288.5	TSL:1	c.*394A>G		3_prime_UTR	Exon 30 of 30	ENSP00000431012.1

Frequencies

GnomAD3 genomes AF: 0.370 AC: 56238 AN: 151976 Hom.: 10640 Cov.: 34

Gnomad AFR AF: 0.336

Gnomad AMI AF: 0.321

Gnomad AMR AF: 0.310

Gnomad ASJ AF: 0.368

Gnomad EAS AF: 0.576

Gnomad SAS AF: 0.437

Gnomad FIN AF: 0.402

Gnomad MID AF: 0.370

Gnomad NFE AF: 0.379

Gnomad OTH AF: 0.388

GnomAD4 exome AF: 0.404 AC: 18503 AN: 45812 Hom.: 3507 Cov.: 0 AF XY: 0.406 AC XY: 9546 AN XY: 23532

African (AFR) AF: 0.329 AC: 399 AN: 1212

American (AMR) AF: 0.322 AC: 1013 AN: 3144

Ashkenazi Jewish (ASJ) AF: 0.373 AC: 515 AN: 1380

East Asian (EAS) AF: 0.586 AC: 1252 AN: 2138

South Asian (SAS) AF: 0.469 AC: 1910 AN: 4076

European-Finnish (FIN) AF: 0.416 AC: 803 AN: 1932

Middle Eastern (MID) AF: 0.452 AC: 95 AN: 210

European-Non Finnish (NFE) AF: 0.395 AC: 11467 AN: 29060

Other (OTH) AF: 0.394 AC: 1049 AN: 2660

GnomAD4 genome AF: 0.370 AC: 56252 AN: 152096 Hom.: 10642 Cov.: 34 AF XY: 0.372 AC XY: 27687 AN XY: 74354

African (AFR) AF: 0.335 AC: 13910 AN: 41494

American (AMR) AF: 0.310 AC: 4736 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.368 AC: 1275 AN: 3464

East Asian (EAS) AF: 0.574 AC: 2972 AN: 5174

South Asian (SAS) AF: 0.437 AC: 2108 AN: 4828

European-Finnish (FIN) AF: 0.402 AC: 4249 AN: 10560

Middle Eastern (MID) AF: 0.371 AC: 109 AN: 294

European-Non Finnish (NFE) AF: 0.379 AC: 25768 AN: 67980

Other (OTH) AF: 0.394 AC: 832 AN: 2114

Alfa AF: 0.375 Hom.: 18391

Bravo AF: 0.364

Asia WGS AF: 0.519 AC: 1808 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.33
DANN	Benign	0.35
PhyloP100		-1.2
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: rs6991392; hg19: chr8-1905823;