8-1869120-G-T

Variant names:

• chr8-1869120-G-T
• rs10503168
• NM_014629.4:c.623-74G>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.623-74G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0299 in 1,305,164 control chromosomes in the GnomAD database, including 1,226 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.057 (473 hom., cov: 33)
  • Exomes 𝑓: 0.026 (753 hom.)
• Consequence: ARHGEF10 NM_014629.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.75
• Publications: 3 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 8-1869120-G-T is Benign according to our data. Variant chr8-1869120-G-T is described in ClinVar as Benign. ClinVar VariationId is 1279705.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.141 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGEF10	NM_014629.4	c.623-74G>T		intron_variant	Intron 6 of 28	ENST00000349830.8	NP_055444.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARHGEF10	ENST00000349830.8	c.623-74G>T		intron_variant	Intron 6 of 28	1	NM_014629.4	ENSP00000340297.3
KBTBD11-OT1	ENST00000635855.1	n.*577-74G>T		intron_variant	Intron 7 of 29	5		ENSP00000489726.1

Frequencies

GnomAD3 genomes AF: 0.0570 AC: 8664 AN: 152030 Hom.: 467 Cov.: 33

Gnomad AFR AF: 0.143

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0288

Gnomad ASJ AF: 0.0144

Gnomad EAS AF: 0.0423

Gnomad SAS AF: 0.00435

Gnomad FIN AF: 0.0452

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0208

Gnomad OTH AF: 0.0503

GnomAD4 exome AF: 0.0263 AC: 30297 AN: 1153016 Hom.: 753 AF XY: 0.0246 AC XY: 14496 AN XY: 589238

African (AFR) AF: 0.152 AC: 4194 AN: 27604

American (AMR) AF: 0.0200 AC: 887 AN: 44332

Ashkenazi Jewish (ASJ) AF: 0.0144 AC: 348 AN: 24226

East Asian (EAS) AF: 0.0549 AC: 2091 AN: 38064

South Asian (SAS) AF: 0.00357 AC: 287 AN: 80364

European-Finnish (FIN) AF: 0.0423 AC: 2254 AN: 53242

Middle Eastern (MID) AF: 0.00906 AC: 47 AN: 5186

European-Non Finnish (NFE) AF: 0.0224 AC: 18610 AN: 829744

Other (OTH) AF: 0.0314 AC: 1579 AN: 50254

GnomAD4 genome AF: 0.0571 AC: 8689 AN: 152148 Hom.: 473 Cov.: 33 AF XY: 0.0571 AC XY: 4249 AN XY: 74356

African (AFR) AF: 0.144 AC: 5964 AN: 41484

American (AMR) AF: 0.0287 AC: 439 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0144 AC: 50 AN: 3466

East Asian (EAS) AF: 0.0417 AC: 216 AN: 5186

South Asian (SAS) AF: 0.00373 AC: 18 AN: 4824

European-Finnish (FIN) AF: 0.0452 AC: 478 AN: 10568

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0208 AC: 1414 AN: 68022

Other (OTH) AF: 0.0498 AC: 105 AN: 2108

Alfa AF: 0.0290 Hom.: 230

Bravo AF: 0.0599

Asia WGS AF: 0.0280 AC: 96 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

May 11, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.011
DANN	Benign	0.77
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: rs10503168; hg19: chr8-1817286;