Variant rs183417070 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.334+7C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000504 in 1,201,508 control chromosomes in the GnomAD database, including 2 homozygotes. There are 169 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0024 ( 1 hom., 58 hem., cov: 20)

Exomes 𝑓: 0.00031 ( 1 hom. 111 hem. )

Consequence

ARHGEF6
NM_004840.3 splice_region, intron

Scores

Splicing: ADA: 0.00006595

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.139

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.87).

BP6

Variant X-136747501-G-A is Benign according to our data. Variant chrX-136747501-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 445824.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Hemizygotes in GnomAd4 at 58 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARHGEF6	NM_004840.3 linkuse as main transcript	c.334+7C>T		splice_region_variant, intron_variant		ENST00000250617.7	NP_004831.1

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Protein	Appris	UniProt
ARHGEF6	ENST00000250617.7 linkuse as main transcript	c.334+7C>T	splice_region_variant, intron_variant	1	NM_004840.3	ENSP00000250617	P1	Q15052-1
ARHGEF6	ENST00000370622.5 linkuse as main transcript	c.-129+7C>T	splice_region_variant, intron_variant	1		ENSP00000359656		Q15052-2
ARHGEF6	ENST00000370620.5 linkuse as main transcript	c.-129+7C>T	splice_region_variant, intron_variant	2		ENSP00000359654		Q15052-2

Frequencies

GnomAD3 genomes

AF:

0.00235

AC:

255

AN:

108478

Hom.:

Cov.:

AF XY:

0.00172

AC XY:

AN XY:

30862

show subpopulations

Gnomad AFR

AF:

0.00800

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000496

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000402

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000172

Gnomad OTH

AF:

0.00206

GnomAD3 exomes

AF:

0.000747

AC:

137

AN:

183300

Hom.:

AF XY:

0.000531

AC XY:

AN XY:

67770

show subpopulations

Gnomad AFR exome

AF:

0.00806

Gnomad AMR exome

AF:

0.000401

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000210

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000171

Gnomad OTH exome

AF:

0.000442

GnomAD4 exome

AF:

0.000315

AC:

344

AN:

1092980

Hom.:

Cov.:

AF XY:

0.000310

AC XY:

111

AN XY:

358628

show subpopulations

Gnomad4 AFR exome

AF:

0.00745

Gnomad4 AMR exome

AF:

0.000512

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000148

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000115

Gnomad4 OTH exome

AF:

0.000501

GnomAD4 genome

AF:

0.00240

AC:

261

AN:

108528

Hom.:

Cov.:

AF XY:

0.00188

AC XY:

AN XY:

30922

show subpopulations

Gnomad4 AFR

AF:

0.00818

Gnomad4 AMR

AF:

0.000495

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000403

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000172

Gnomad4 OTH

AF:

0.00204

Alfa

AF:

0.00104

Hom.:

Bravo

AF:

0.00246

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 04, 2017	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

0.71

DANN

Benign

0.73

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000066

dbscSNV1_RF

Benign

0.0060

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

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