rs5974620

chrX-136708707-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004840.3(ARHGEF6):c.891G>T(p.Gln297His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00156 in 1,205,188 control chromosomes in the GnomAD database, including 19 homozygotes. There are 498 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 0.0080 (8 hom., 239 hem., cov: 23)
  • Exomes 𝑓: 0.00090 (11 hom. 259 hem.)
• Consequence: ARHGEF6 NM_004840.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.17

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.019119442).
• BP6: Variant X-136708707-C-A is Benign according to our data. Variant chrX-136708707-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 446067.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-136708707-C-A is described in Lovd as [Benign]. Variant chrX-136708707-C-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00802 (897/111855) while in subpopulation AFR AF= 0.0275 (848/30801). AF 95% confidence interval is 0.026. There are 8 homozygotes in gnomad4. There are 239 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 8 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARHGEF6	NM_004840.3	c.891G>T	p.Gln297His	missense_variant	8/22	ENST00000250617.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARHGEF6	ENST00000250617.7	c.891G>T	p.Gln297His	missense_variant	8/22	1	NM_004840.3	P1
ARHGEF6	ENST00000370622.5	c.429G>T	p.Gln143His	missense_variant	7/21	1
ARHGEF6	ENST00000370620.5	c.429G>T	p.Gln143His	missense_variant	7/21	2

Frequencies

GnomAD3 genomes AF: 0.00803 AC: 898 AN: 111803 Hom.: 8 Cov.: 23 AF XY: 0.00703 AC XY: 239 AN XY: 34013

Gnomad AFR AF: 0.0276

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00294

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000753

Gnomad OTH AF: 0.00929

GnomAD3 exomes AF: 0.00237 AC: 434 AN: 183285 Hom.: 3 AF XY: 0.00152 AC XY: 103 AN XY: 67761

Gnomad AFR exome AF: 0.0306

Gnomad AMR exome AF: 0.000875

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000525

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000245

Gnomad OTH exome AF: 0.00111

GnomAD4 exome AF: 0.000895 AC: 979 AN: 1093333 Hom.: 11 Cov.: 29 AF XY: 0.000721 AC XY: 259 AN XY: 359219

Gnomad4 AFR exome AF: 0.0312

Gnomad4 AMR exome AF: 0.00128

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000926

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000107

Gnomad4 OTH exome AF: 0.00212

GnomAD4 genome AF: 0.00802 AC: 897 AN: 111855 Hom.: 8 Cov.: 23 AF XY: 0.00701 AC XY: 239 AN XY: 34075

Gnomad4 AFR AF: 0.0275

Gnomad4 AMR AF: 0.00294

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000753

Gnomad4 OTH AF: 0.00917

Alfa AF: 0.00135 Hom.: 50

Bravo AF: 0.00968

ESP6500AA AF: 0.0282 AC: 108

ESP6500EA AF: 0.000149 AC: 1

ExAC AF: 0.00270 AC: 328

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

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	Apr 19, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 12, 2015

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.16
Cadd	Benign	21
Dann	Uncertain	1.0
FATHMM_MKL	Uncertain	0.86	D
MetaRNN	Benign	0.019	T;T;T
MetaSVM	Benign	-0.40	T
MutationTaster	Benign	0.000071	P;P;P;P
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-3.7	D;D;D
REVEL	Benign	0.27
Sift	Benign	0.088	T;T;T
Sift4G	Benign	0.072	T;T;T
Polyphen		0.88	.;.;P
Vest4		0.32
MutPred		0.17		.;.;Gain of catalytic residue at L299 (P = 0.0589);
MVP		0.84
MPC		0.28
ClinPred		0.037	T
GERP RS		2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.86
gMVP		0.42

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs5974620; hg19: chrX-135790866;