8-1843267-C-T

Variant names:

• chr8-1843267-C-T
• rs11136431
• NM_014629.4:c.-47-86C>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.-47-86C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.535 in 961,384 control chromosomes in the GnomAD database, including 141,958 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.46 (17758 hom., cov: 32)
  • Exomes 𝑓: 0.55 (124200 hom.)
• Consequence: ARHGEF10 NM_014629.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.530
• Publications: 15 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=-0.91).
• BP6: Variant 8-1843267-C-T is Benign according to our data. Variant chr8-1843267-C-T is described in ClinVar as Benign. ClinVar VariationId is 1244753.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.579 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGEF10	NM_014629.4	c.-47-86C>T		intron_variant	Intron 1 of 28	ENST00000349830.8	NP_055444.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARHGEF10	ENST00000349830.8	c.-47-86C>T		intron_variant	Intron 1 of 28	1	NM_014629.4	ENSP00000340297.3
KBTBD11-OT1	ENST00000635855.1	n.544-86C>T		intron_variant	Intron 2 of 29	5		ENSP00000489726.1

Frequencies

GnomAD3 genomes AF: 0.461 AC: 70022 AN: 151876 Hom.: 17759 Cov.: 32

Gnomad AFR AF: 0.251

Gnomad AMI AF: 0.718

Gnomad AMR AF: 0.401

Gnomad ASJ AF: 0.443

Gnomad EAS AF: 0.459

Gnomad SAS AF: 0.598

Gnomad FIN AF: 0.561

Gnomad MID AF: 0.452

Gnomad NFE AF: 0.575

Gnomad OTH AF: 0.445

GnomAD4 exome AF: 0.548 AC: 443820 AN: 809390 Hom.: 124200 AF XY: 0.551 AC XY: 230251 AN XY: 417842

African (AFR) AF: 0.246 AC: 5038 AN: 20458

American (AMR) AF: 0.384 AC: 13206 AN: 34426

Ashkenazi Jewish (ASJ) AF: 0.451 AC: 9647 AN: 21410

East Asian (EAS) AF: 0.491 AC: 16149 AN: 32902

South Asian (SAS) AF: 0.579 AC: 38976 AN: 67312

European-Finnish (FIN) AF: 0.595 AC: 20864 AN: 35074

Middle Eastern (MID) AF: 0.456 AC: 1721 AN: 3778

European-Non Finnish (NFE) AF: 0.573 AC: 318041 AN: 555316

Other (OTH) AF: 0.521 AC: 20178 AN: 38714

GnomAD4 genome AF: 0.461 AC: 70045 AN: 151994 Hom.: 17758 Cov.: 32 AF XY: 0.463 AC XY: 34369 AN XY: 74300

African (AFR) AF: 0.251 AC: 10410 AN: 41422

American (AMR) AF: 0.400 AC: 6118 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.443 AC: 1537 AN: 3470

East Asian (EAS) AF: 0.458 AC: 2368 AN: 5168

South Asian (SAS) AF: 0.598 AC: 2874 AN: 4810

European-Finnish (FIN) AF: 0.561 AC: 5935 AN: 10580

Middle Eastern (MID) AF: 0.452 AC: 132 AN: 292

European-Non Finnish (NFE) AF: 0.575 AC: 39069 AN: 67956

Other (OTH) AF: 0.449 AC: 947 AN: 2108

Alfa AF: 0.517 Hom.: 55276

Bravo AF: 0.434

Asia WGS AF: 0.539 AC: 1874 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 10, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	3.8
DANN	Benign	0.62
PhyloP100		-0.53
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: rs11136431; hg19: chr8-1791433;