chr8-1932364-T-C

Variant names:

• chr8-1932364-T-C
• rs4242548
• NM_014629.4:c.3080-1436T>C

Variant summary

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

The NM_014629.4(ARHGEF10):​c.3080-1436T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.446 in 152,130 control chromosomes in the GnomAD database, including 15,883 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 0.45 (15883 hom., cov: 34)
• Consequence: ARHGEF10 NM_014629.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.387
• Publications: 2 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=-0.88).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.831 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGEF10	NM_014629.4	MANE Select	c.3080-1436T>C		intron	N/A	NP_055444.2
	ARHGEF10	NM_001438091.1		c.3083-1436T>C		intron	N/A	NP_001425020.1
	ARHGEF10	NM_001308153.3		c.3080-1436T>C		intron	N/A	NP_001295082.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGEF10	ENST00000349830.8	TSL:1 MANE Select	c.3080-1436T>C		intron	N/A	ENSP00000340297.3
	ARHGEF10	ENST00000518288.5	TSL:1	c.3152-1436T>C		intron	N/A	ENSP00000431012.1
	ARHGEF10	ENST00000520359.5	TSL:1	c.2966-1436T>C		intron	N/A	ENSP00000427909.1

Frequencies

GnomAD3 genomes AF: 0.446 AC: 67854 AN: 152012 Hom.: 15867 Cov.: 34

Gnomad AFR AF: 0.346

Gnomad AMI AF: 0.457

Gnomad AMR AF: 0.433

Gnomad ASJ AF: 0.469

Gnomad EAS AF: 0.853

Gnomad SAS AF: 0.571

Gnomad FIN AF: 0.542

Gnomad MID AF: 0.443

Gnomad NFE AF: 0.455

Gnomad OTH AF: 0.442

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

GnomAD4 genome AF: 0.446 AC: 67906 AN: 152130 Hom.: 15883 Cov.: 34 AF XY: 0.456 AC XY: 33943 AN XY: 74378

African (AFR) AF: 0.346 AC: 14370 AN: 41496

American (AMR) AF: 0.432 AC: 6618 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.469 AC: 1626 AN: 3470

East Asian (EAS) AF: 0.852 AC: 4396 AN: 5158

South Asian (SAS) AF: 0.571 AC: 2757 AN: 4830

European-Finnish (FIN) AF: 0.542 AC: 5750 AN: 10600

Middle Eastern (MID) AF: 0.442 AC: 130 AN: 294

European-Non Finnish (NFE) AF: 0.455 AC: 30898 AN: 67954

Other (OTH) AF: 0.447 AC: 945 AN: 2116

Alfa AF: 0.446 Hom.: 23064

Bravo AF: 0.434

Asia WGS AF: 0.696 AC: 2420 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.9
DANN	Benign	0.66
PhyloP100		-0.39
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: rs4242548; hg19: chr8-1880530;