8-1843506-C-T

Variant names:

• chr8-1843506-C-T
• rs11136434
• NM_014629.4:c.37+70C>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+70C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.482 in 1,227,974 control chromosomes in the GnomAD database, including 144,564 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.42 (13954 hom., cov: 32)
  • Exomes 𝑓: 0.49 (130610 hom.)
• Consequence: ARHGEF10 NM_014629.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.464
• Publications: 4 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: AD, Unknown Classification: SUPPORTIVE, LIMITED Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), 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=-0.97).
• BP6: Variant 8-1843506-C-T is Benign according to our data. Variant chr8-1843506-C-T is described in ClinVar as Benign. ClinVar VariationId is 1279597.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.496 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+70C>T		intron	N/A	NP_055444.2	O15013-5
	ARHGEF10	NM_001438091.1		c.37+70C>T		intron	N/A	NP_001425020.1
	ARHGEF10	NM_001308153.3		c.37+70C>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+70C>T		intron	N/A	ENSP00000340297.3	O15013-5
	ARHGEF10	ENST00000518288.5	TSL:1	c.109+70C>T		intron	N/A	ENSP00000431012.1	O15013-6
	ARHGEF10	ENST00000520359.5	TSL:1	c.37+70C>T		intron	N/A	ENSP00000427909.1	O15013-7

Frequencies

GnomAD3 genomes AF: 0.417 AC: 63223 AN: 151640 Hom.: 13952 Cov.: 32

Gnomad AFR AF: 0.288

Gnomad AMI AF: 0.636

Gnomad AMR AF: 0.347

Gnomad ASJ AF: 0.388

Gnomad EAS AF: 0.395

Gnomad SAS AF: 0.445

Gnomad FIN AF: 0.484

Gnomad MID AF: 0.351

Gnomad NFE AF: 0.500

Gnomad OTH AF: 0.387

GnomAD4 exome AF: 0.491 AC: 528126 AN: 1076216 Hom.: 130610 AF XY: 0.487 AC XY: 267683 AN XY: 549806

African (AFR) AF: 0.287 AC: 7238 AN: 25194

American (AMR) AF: 0.336 AC: 13425 AN: 39980

Ashkenazi Jewish (ASJ) AF: 0.396 AC: 9260 AN: 23356

East Asian (EAS) AF: 0.424 AC: 15515 AN: 36572

South Asian (SAS) AF: 0.431 AC: 32454 AN: 75362

European-Finnish (FIN) AF: 0.523 AC: 24901 AN: 47646

Middle Eastern (MID) AF: 0.351 AC: 1437 AN: 4090

European-Non Finnish (NFE) AF: 0.517 AC: 401821 AN: 776496

Other (OTH) AF: 0.465 AC: 22075 AN: 47520

GnomAD4 genome AF: 0.417 AC: 63249 AN: 151758 Hom.: 13954 Cov.: 32 AF XY: 0.415 AC XY: 30814 AN XY: 74184

African (AFR) AF: 0.288 AC: 11944 AN: 41444

American (AMR) AF: 0.347 AC: 5303 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.388 AC: 1347 AN: 3472

East Asian (EAS) AF: 0.395 AC: 2025 AN: 5128

South Asian (SAS) AF: 0.444 AC: 2137 AN: 4814

European-Finnish (FIN) AF: 0.484 AC: 5087 AN: 10508

Middle Eastern (MID) AF: 0.344 AC: 101 AN: 294

European-Non Finnish (NFE) AF: 0.500 AC: 33904 AN: 67812

Other (OTH) AF: 0.392 AC: 827 AN: 2110

Alfa AF: 0.464 Hom.: 2105

Bravo AF: 0.397

Asia WGS AF: 0.450 AC: 1565 AN: 3478

ClinVar

ClinVar submissions

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	-0.97
CADD	Benign	1.4
DANN	Benign	0.33
PhyloP100		-0.46
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: rs11136434; hg19: chr8-1791672; COSMIC: COSV50669899;