8-1917721-A-G

Variant names:

• chr8-1917721-A-G
• rs7004405
• NM_014629.4:c.2144-5243A>G

Variant summary

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

The NM_014629.4(ARHGEF10):​c.2144-5243A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.467 in 152,112 control chromosomes in the GnomAD database, including 17,220 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 0.47 (17220 hom., cov: 33)
• Consequence: ARHGEF10 NM_014629.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.973
• Publications: 5 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=-0.86).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.739 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGEF10	NM_014629.4	c.2144-5243A>G		intron_variant	Intron 18 of 28	ENST00000349830.8	NP_055444.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARHGEF10	ENST00000349830.8	c.2144-5243A>G		intron_variant	Intron 18 of 28	1	NM_014629.4	ENSP00000340297.3
KBTBD11-OT1	ENST00000635855.1	n.*2098-5243A>G		intron_variant	Intron 19 of 29	5		ENSP00000489726.1

Frequencies

GnomAD3 genomes AF: 0.467 AC: 71049 AN: 151994 Hom.: 17226 Cov.: 33

Gnomad AFR AF: 0.374

Gnomad AMI AF: 0.421

Gnomad AMR AF: 0.480

Gnomad ASJ AF: 0.434

Gnomad EAS AF: 0.759

Gnomad SAS AF: 0.628

Gnomad FIN AF: 0.542

Gnomad MID AF: 0.386

Gnomad NFE AF: 0.479

Gnomad OTH AF: 0.465

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.467 AC: 71059 AN: 152112 Hom.: 17220 Cov.: 33 AF XY: 0.474 AC XY: 35214 AN XY: 74366

African (AFR) AF: 0.374 AC: 15497 AN: 41490

American (AMR) AF: 0.480 AC: 7337 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.434 AC: 1506 AN: 3470

East Asian (EAS) AF: 0.759 AC: 3923 AN: 5172

South Asian (SAS) AF: 0.627 AC: 3025 AN: 4824

European-Finnish (FIN) AF: 0.542 AC: 5731 AN: 10580

Middle Eastern (MID) AF: 0.395 AC: 116 AN: 294

European-Non Finnish (NFE) AF: 0.479 AC: 32560 AN: 67978

Other (OTH) AF: 0.466 AC: 981 AN: 2104

Alfa AF: 0.473 Hom.: 29361

Bravo AF: 0.459

Asia WGS AF: 0.665 AC: 2310 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	4.8
DANN	Benign	0.62
PhyloP100		0.97
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: rs7004405; hg19: chr8-1865887;