8-1843496-C-T

Variant names:

• chr8-1843496-C-T
• rs74415378
• NM_014629.4:c.37+60C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_014629.4(ARHGEF10):​c.37+60C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.114 in 1,337,902 control chromosomes in the GnomAD database, including 10,303 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1152 hom., cov: 32)
  • Exomes 𝑓: 0.11 (9151 hom.)
• Consequence: ARHGEF10 NM_014629.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.70
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 8-1843496-C-T is Benign according to our data. Variant chr8-1843496-C-T is described in ClinVar as Benign. ClinVar VariationId is 1288449.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.228 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGEF10	NM_014629.4	MANE Select	c.37+60C>T		intron	N/A	NP_055444.2	O15013-5
	ARHGEF10	NM_001438091.1		c.37+60C>T		intron	N/A	NP_001425020.1
	ARHGEF10	NM_001308153.3		c.37+60C>T		intron	N/A	NP_001295082.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGEF10	ENST00000349830.8	TSL:1 MANE Select	c.37+60C>T		intron	N/A	ENSP00000340297.3	O15013-5
	ARHGEF10	ENST00000518288.5	TSL:1	c.109+60C>T		intron	N/A	ENSP00000431012.1	O15013-6
	ARHGEF10	ENST00000520359.5	TSL:1	c.37+60C>T		intron	N/A	ENSP00000427909.1	O15013-7

Frequencies

GnomAD3 genomes AF: 0.113 AC: 17235 AN: 151986 Hom.: 1145 Cov.: 32

Gnomad AFR AF: 0.0875

Gnomad AMI AF: 0.0811

Gnomad AMR AF: 0.204

Gnomad ASJ AF: 0.0926

Gnomad EAS AF: 0.240

Gnomad SAS AF: 0.180

Gnomad FIN AF: 0.102

Gnomad MID AF: 0.127

Gnomad NFE AF: 0.0973

Gnomad OTH AF: 0.125

GnomAD4 exome AF: 0.114 AC: 135082 AN: 1185798 Hom.: 9151 AF XY: 0.116 AC XY: 70029 AN XY: 601588

African (AFR) AF: 0.0856 AC: 2370 AN: 27702

American (AMR) AF: 0.237 AC: 9897 AN: 41802

Ashkenazi Jewish (ASJ) AF: 0.0978 AC: 2365 AN: 24170

East Asian (EAS) AF: 0.261 AC: 9812 AN: 37632

South Asian (SAS) AF: 0.179 AC: 14059 AN: 78540

European-Finnish (FIN) AF: 0.0895 AC: 4454 AN: 49750

Middle Eastern (MID) AF: 0.120 AC: 546 AN: 4568

European-Non Finnish (NFE) AF: 0.0983 AC: 85554 AN: 870504

Other (OTH) AF: 0.118 AC: 6025 AN: 51130

GnomAD4 genome AF: 0.114 AC: 17272 AN: 152104 Hom.: 1152 Cov.: 32 AF XY: 0.118 AC XY: 8808 AN XY: 74334

African (AFR) AF: 0.0881 AC: 3657 AN: 41516

American (AMR) AF: 0.204 AC: 3118 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.0926 AC: 321 AN: 3466

East Asian (EAS) AF: 0.239 AC: 1233 AN: 5154

South Asian (SAS) AF: 0.180 AC: 867 AN: 4814

European-Finnish (FIN) AF: 0.102 AC: 1083 AN: 10590

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

European-Non Finnish (NFE) AF: 0.0973 AC: 6618 AN: 67984

Other (OTH) AF: 0.125 AC: 262 AN: 2104

Alfa AF: 0.105 Hom.: 567

Bravo AF: 0.123

Asia WGS AF: 0.195 AC: 680 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	6.7
DANN	Benign	0.43
PhyloP100		1.7
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: rs74415378; hg19: chr8-1791662; COSMIC: COSV50697265;