rs4876271

Variant names:

• chr8-1953764-G-A
• rs4876271
• NM_014629.4:c.3520+937G>A

Variant summary

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

The NM_014629.4(ARHGEF10):​c.3520+937G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.138 in 152,196 control chromosomes in the GnomAD database, including 1,440 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 0.14 (1440 hom., cov: 33)
• Consequence: ARHGEF10 NM_014629.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.325
• 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=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.213 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.3520+937G>A		intron	N/A	NP_055444.2
	ARHGEF10	NM_001438091.1		c.3523+937G>A		intron	N/A	NP_001425020.1
	ARHGEF10	NM_001308153.3		c.3520+937G>A		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.3520+937G>A		intron	N/A	ENSP00000340297.3
	ARHGEF10	ENST00000518288.5	TSL:1	c.3592+937G>A		intron	N/A	ENSP00000431012.1
	ARHGEF10	ENST00000520359.5	TSL:1	c.3406+937G>A		intron	N/A	ENSP00000427909.1

Frequencies

GnomAD3 genomes AF: 0.138 AC: 21023 AN: 152078 Hom.: 1441 Cov.: 33

Gnomad AFR AF: 0.140

Gnomad AMI AF: 0.185

Gnomad AMR AF: 0.175

Gnomad ASJ AF: 0.135

Gnomad EAS AF: 0.223

Gnomad SAS AF: 0.136

Gnomad FIN AF: 0.143

Gnomad MID AF: 0.0791

Gnomad NFE AF: 0.122

Gnomad OTH AF: 0.125

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

GnomAD4 genome AF: 0.138 AC: 21030 AN: 152196 Hom.: 1440 Cov.: 33 AF XY: 0.140 AC XY: 10395 AN XY: 74402

African (AFR) AF: 0.140 AC: 5816 AN: 41522

American (AMR) AF: 0.175 AC: 2674 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.135 AC: 467 AN: 3472

East Asian (EAS) AF: 0.224 AC: 1157 AN: 5166

South Asian (SAS) AF: 0.135 AC: 651 AN: 4828

European-Finnish (FIN) AF: 0.143 AC: 1519 AN: 10586

Middle Eastern (MID) AF: 0.0748 AC: 22 AN: 294

European-Non Finnish (NFE) AF: 0.122 AC: 8293 AN: 68004

Other (OTH) AF: 0.124 AC: 262 AN: 2112

Alfa AF: 0.127 Hom.: 1652

Bravo AF: 0.145

Asia WGS AF: 0.163 AC: 564 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	2.6
DANN	Benign	0.55
PhyloP100		-0.33
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: rs4876271; hg19: chr8-1901930;