X-136675035-G-A

Variant names:

• chrX-136675035-G-A
• rs12008084
• NM_004840.3:c.2007C>T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_004840.3(ARHGEF6):​c.2007C>T​(p.Ser669Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00413 in 1,209,600 control chromosomes in the GnomAD database, including 128 homozygotes. There are 1,339 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.022 (72 hom., 667 hem., cov: 22)
  • Exomes 𝑓: 0.0023 (56 hom. 672 hem.)
• Consequence: ARHGEF6 NM_004840.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.216

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant X-136675035-G-A is Benign according to our data. Variant chrX-136675035-G-A is described in ClinVar as [Benign]. Clinvar id is 128449.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.216 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0724 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGEF6	NM_004840.3	c.2007C>T	p.Ser669Ser	synonymous_variant	Exon 19 of 22	ENST00000250617.7	NP_004831.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARHGEF6	ENST00000250617.7	c.2007C>T	p.Ser669Ser	synonymous_variant	Exon 19 of 22	1	NM_004840.3	ENSP00000250617.6
ARHGEF6	ENST00000370622.5	c.1545C>T	p.Ser515Ser	synonymous_variant	Exon 18 of 21	1		ENSP00000359656.1
ARHGEF6	ENST00000370620.5	c.1545C>T	p.Ser515Ser	synonymous_variant	Exon 18 of 21	2		ENSP00000359654.1

Frequencies

GnomAD3 genomes AF: 0.0219 AC: 2452 AN: 111773 Hom.: 72 Cov.: 22 AF XY: 0.0195 AC XY: 662 AN XY: 33979

Gnomad AFR AF: 0.0749

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0111

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000747

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000226

Gnomad OTH AF: 0.0159

GnomAD3 exomes AF: 0.00676 AC: 1239 AN: 183343 Hom.: 36 AF XY: 0.00398 AC XY: 270 AN XY: 67775

Gnomad AFR exome AF: 0.0807

Gnomad AMR exome AF: 0.00489

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000158

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000244

Gnomad OTH exome AF: 0.00486

GnomAD4 exome AF: 0.00231 AC: 2536 AN: 1097773 Hom.: 56 Cov.: 30 AF XY: 0.00185 AC XY: 672 AN XY: 363141

Gnomad4 AFR exome AF: 0.0732

Gnomad4 AMR exome AF: 0.00506

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000331

Gnomad4 SAS exome AF: 0.000222

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000210

Gnomad4 OTH exome AF: 0.00490

GnomAD4 genome AF: 0.0220 AC: 2457 AN: 111827 Hom.: 72 Cov.: 22 AF XY: 0.0196 AC XY: 667 AN XY: 34043

Gnomad4 AFR AF: 0.0749

Gnomad4 AMR AF: 0.0111

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000750

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000226

Gnomad4 OTH AF: 0.0157

Alfa AF: 0.0141 Hom.: 82

Bravo AF: 0.0265

EpiCase AF: 0.000109

EpiControl AF: 0.000178

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

-

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Dec 13, 2014

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided Benign:2

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

ARHGEF6-related disorder Benign:1

Aug 07, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as 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	-0.86
CADD	Benign	0.37
DANN	Benign	0.40

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs12008084; hg19: chrX-135757194;