rs140322310

chrX-136779508-A-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_004840.3(ARHGEF6):c.166-11T>C variant causes a splice polypyrimidine tract, intron change. The variant allele was found at a frequency of 0.003 in 1,192,114 control chromosomes in the GnomAD database, including 7 homozygotes. There are 1,149 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0018 (0 hom., 64 hem., cov: 23)
  • Exomes 𝑓: 0.0031 (7 hom. 1085 hem.)
• Consequence: ARHGEF6 NM_004840.3 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.3443
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts P:1 B:2
• Conservation: PhyloP100: 6.26

Genes affected

ARHGEF6 (HGNC:685): (Rac/Cdc42 guanine nucleotide exchange factor 6) Rho GTPases play a fundamental role in numerous cellular processes that are initiated by extracellular stimuli that work through G protein coupled receptors. The encoded protein belongs to a family of cytoplasmic proteins that activate the Ras-like family of Rho proteins by exchanging bound GDP for GTP. It may form a complex with G proteins and stimulate Rho-dependent signals. This protein is activated by PI3-kinase. Mutations in this gene can cause X-chromosomal non-specific cognitive disability. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant X-136779508-A-G is Benign according to our data. Variant chrX-136779508-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 367947.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-136779508-A-G is described in Lovd as [Likely_benign].
• BS2: High Hemizygotes in GnomAd at 64 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARHGEF6	NM_004840.3	c.166-11T>C		splice_polypyrimidine_tract_variant, intron_variant		ENST00000250617.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARHGEF6	ENST00000250617.7	c.166-11T>C		splice_polypyrimidine_tract_variant, intron_variant		1	NM_004840.3	P1

Frequencies

GnomAD3 genomes AF: 0.00176 AC: 197 AN: 111856 Hom.: 0 Cov.: 23 AF XY: 0.00188 AC XY: 64 AN XY: 34000

Gnomad AFR AF: 0.000586

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000381

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000369

Gnomad FIN AF: 0.00116

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00310

Gnomad OTH AF: 0.00132

GnomAD3 exomes AF: 0.00164 AC: 300 AN: 183335 Hom.: 1 AF XY: 0.00161 AC XY: 109 AN XY: 67791

Gnomad AFR exome AF: 0.000456

Gnomad AMR exome AF: 0.000146

Gnomad ASJ exome AF: 0.000134

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000157

Gnomad FIN exome AF: 0.00200

Gnomad NFE exome AF: 0.00304

Gnomad OTH exome AF: 0.00110

GnomAD4 exome AF: 0.00313 AC: 3377 AN: 1080204 Hom.: 7 Cov.: 28 AF XY: 0.00313 AC XY: 1085 AN XY: 347134

Gnomad4 AFR exome AF: 0.000230

Gnomad4 AMR exome AF: 0.000199

Gnomad4 ASJ exome AF: 0.000208

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000317

Gnomad4 FIN exome AF: 0.00197

Gnomad4 NFE exome AF: 0.00383

Gnomad4 OTH exome AF: 0.00215

GnomAD4 genome AF: 0.00176 AC: 197 AN: 111910 Hom.: 0 Cov.: 23 AF XY: 0.00188 AC XY: 64 AN XY: 34064

Gnomad4 AFR AF: 0.000585

Gnomad4 AMR AF: 0.000381

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000370

Gnomad4 FIN AF: 0.00116

Gnomad4 NFE AF: 0.00310

Gnomad4 OTH AF: 0.00130

Alfa AF: 0.00292 Hom.: 69

Bravo AF: 0.00175

ClinVar

Significance: Likely benign

Submissions summary: Pathogenic:1 Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Intellectual disability, X-linked 46 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 01, 2000

- -

ARHGEF6-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 06, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Aug 02, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
Cadd	Benign	19
Dann	Benign	0.81

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.34
dbscSNV1_RF	Benign	0.31
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs140322310; hg19: chrX-135861667;