Variant rs140322310 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_004840.3(ARHGEF6):c.166-11T>C variant causes a 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 intron

Scores

Splicing: ADA: 0.3443

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1B:3

Conservation

PhyloP100: 6.26

Variant links:

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]

ARHGEF6 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 GnomAd4 at 64 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARHGEF6	NM_004840.3 linkuse as main transcript	c.166-11T>C		intron_variant		ENST00000250617.7	NP_004831.1	Q15052-1Q8N4Q3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARHGEF6	ENST00000250617.7 linkuse as main transcript	c.166-11T>C		intron_variant		1	NM_004840.3	ENSP00000250617.6		Q15052-1

Frequencies

GnomAD3 genomes

AF:

0.00176

AC:

197

AN:

111856

Hom.:

Cov.:

AF XY:

0.00188

AC XY:

AN XY:

34000

show subpopulations

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.:

AF XY:

0.00161

AC XY:

109

AN XY:

67791

show subpopulations

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.:

Cov.:

AF XY:

0.00313

AC XY:

1085

AN XY:

347134

show subpopulations

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.:

Cov.:

AF XY:

0.00188

AC XY:

AN XY:

34064

show subpopulations

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.:

Bravo

AF:

0.00175

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	ARHGEF6: BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Aug 02, 2017	- -

Intellectual disability, X-linked 46

Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

OMIM

Oct 01, 2000

- -

ARHGEF6-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 27, 2024

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). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.66

CADD

Benign

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over