rs5974620

Variant names:

• chrX-136708707-C-A
• rs5974620
• NM_004840.3:c.891G>T

Your query was ambiguous. Multiple possible variants found:

• chrX-136708707-C-A
• chrX-136708707-C-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001440994.1(ARHGEF6):​c.972G>T​(p.Gln324His) 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_001440994.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.17
• Publications: 5 publications found

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 Gene-Disease associations (from GenCC):

• non-syndromic X-linked intellectual disability

  Inheritance: XL Classification: SUPPORTIVE, LIMITED, NO_KNOWN Submitted by: Orphanet, ClinGen, Illumina
• complex neurodevelopmental disorder

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• congenital anomaly of kidney and urinary tract

  Inheritance: XL Classification: LIMITED Submitted by: Ambry Genetics
• intellectual disability, X-linked 46

  Inheritance: XL Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P
• X-linked intellectual disability

  Inheritance: XL Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 446067.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High AC in GnomAd4 at 897 XL,AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001440994.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGEF6	NM_004840.3	MANE Select	c.891G>T	p.Gln297His	missense	Exon 8 of 22	NP_004831.1
	ARHGEF6	NM_001440994.1		c.972G>T	p.Gln324His	missense	Exon 9 of 23	NP_001427923.1
	ARHGEF6	NM_001440995.1		c.891G>T	p.Gln297His	missense	Exon 8 of 22	NP_001427924.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGEF6	ENST00000250617.7	TSL:1 MANE Select	c.891G>T	p.Gln297His	missense	Exon 8 of 22	ENSP00000250617.6
	ARHGEF6	ENST00000370622.5	TSL:1	c.429G>T	p.Gln143His	missense	Exon 7 of 21	ENSP00000359656.1
	ARHGEF6	ENST00000881407.1		c.972G>T	p.Gln324His	missense	Exon 9 of 23	ENSP00000551466.1

Frequencies

GnomAD3 genomes AF: 0.00803 AC: 898 AN: 111803 Hom.: 8 Cov.: 23

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

GnomAD2 exomes AF: 0.00237 AC: 434 AN: 183285 AF XY: 0.00152

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 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

African (AFR) AF: 0.0312 AC: 820 AN: 26279

American (AMR) AF: 0.00128 AC: 45 AN: 35125

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19266

East Asian (EAS) AF: 0.00 AC: 0 AN: 29982

South Asian (SAS) AF: 0.0000926 AC: 5 AN: 53983

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40264

Middle Eastern (MID) AF: 0.000729 AC: 3 AN: 4115

European-Non Finnish (NFE) AF: 0.0000107 AC: 9 AN: 838471

Other (OTH) AF: 0.00212 AC: 97 AN: 45848

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

African (AFR) AF: 0.0275 AC: 848 AN: 30801

American (AMR) AF: 0.00294 AC: 31 AN: 10558

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2631

East Asian (EAS) AF: 0.00 AC: 0 AN: 3556

South Asian (SAS) AF: 0.00 AC: 0 AN: 2703

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6027

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 218

European-Non Finnish (NFE) AF: 0.0000753 AC: 4 AN: 53149

Other (OTH) AF: 0.00917 AC: 14 AN: 1526

Alfa AF: 0.00204 Hom.: 90

Bravo AF: 0.00968

ESP6500AA AF: 0.0282 AC: 108

ESP6500EA AF: 0.000149 AC: 1

ExAC AF: 0.00270 AC: 328

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
DEOGEN2	Uncertain	0.54	D
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.85	D
MetaRNN	Benign	0.019	T
MetaSVM	Benign	-0.40	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		1.2
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-3.7	D
REVEL	Benign	0.27
Sift	Benign	0.088	T
Sift4G	Benign	0.072	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
Mutation Taster		=90/10	polymorphism (auto)

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

Other links and lift over

dbSNP: rs5974620; hg19: chrX-135790866;