rs183417070

chrX-136747501-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

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, single submitter B:1
• Conservation: PhyloP100: 0.139

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 -10 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_single_submitter, 1 stars.
• BS2: High Hemizygotes in GnomAd at 53 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARHGEF6	NM_004840.3	c.334+7C>T		splice_region_variant, intron_variant		ENST00000250617.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARHGEF6	ENST00000250617.7	c.334+7C>T		splice_region_variant, intron_variant		1	NM_004840.3	P1
ARHGEF6	ENST00000370622.5	c.-129+7C>T		splice_region_variant, intron_variant		1
ARHGEF6	ENST00000370620.5	c.-129+7C>T		splice_region_variant, intron_variant		2

Frequencies

GnomAD3 genomes AF: 0.00235 AC: 255 AN: 108478 Hom.: 1 Cov.: 20 AF XY: 0.00172 AC XY: 53 AN XY: 30862

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.: 0 AF XY: 0.000531 AC XY: 36 AN XY: 67770

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.: 1 Cov.: 29 AF XY: 0.000310 AC XY: 111 AN XY: 358628

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.: 1 Cov.: 20 AF XY: 0.00188 AC XY: 58 AN XY: 30922

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.: 3

Bravo AF: 0.00246

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

May 04, 2017

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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

Other links and lift over

dbSNP: rs183417070; hg19: chrX-135829660;