rs140322310

Variant names:

• chrX-136779508-A-G
• rs140322310
• NM_004840.3:c.166-11T>C

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_004840.3(ARHGEF6):​c.166-11T>C variant causes a intron change. The variant allele was found at a frequency of 0.003 in 1,192,114 control chromosomes in the GnomAD database, including 7 homozygotes. There are 1,149 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 0.0018 (0 hom., 64 hem., cov: 23)
  • Exomes 𝑓: 0.0031 (7 hom. 1085 hem.)
• Consequence: ARHGEF6 NM_004840.3 intron
• Scores: Splicing: ADA: 0.3443
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:3
• Conservation: PhyloP100: 6.26
• Publications: 0 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: Illumina, Orphanet, ClinGen
• 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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant X-136779508-A-G is Benign according to our data. Variant chrX-136779508-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 367947.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 197 XL,AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004840.3. 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.166-11T>C		intron	N/A	NP_004831.1	Q15052-1
	ARHGEF6	NM_001440994.1		c.166-11T>C		intron	N/A	NP_001427923.1
	ARHGEF6	NM_001440995.1		c.166-11T>C		intron	N/A	NP_001427924.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGEF6	ENST00000250617.7	TSL:1 MANE Select	c.166-11T>C		intron	N/A	ENSP00000250617.6	Q15052-1
	ARHGEF6	ENST00000881407.1		c.166-11T>C		intron	N/A	ENSP00000551466.1
	ARHGEF6	ENST00000881408.1		c.166-11T>C		intron	N/A	ENSP00000551467.1

Frequencies

GnomAD3 genomes AF: 0.00176 AC: 197 AN: 111856 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.000586

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000381

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000369

Gnomad FIN AF: 0.00116

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00310

Gnomad OTH AF: 0.00132

GnomAD2 exomes AF: 0.00164 AC: 300 AN: 183335 AF XY: 0.00161

Gnomad AFR exome AF: 0.000456

Gnomad AMR exome AF: 0.000146

Gnomad ASJ exome AF: 0.000134

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00200

Gnomad NFE exome AF: 0.00304

Gnomad OTH exome AF: 0.00110

GnomAD4 exome AF: 0.00313 AC: 3377 AN: 1080204 Hom.: 7 Cov.: 28 AF XY: 0.00313 AC XY: 1085 AN XY: 347134

African (AFR) AF: 0.000230 AC: 6 AN: 26067

American (AMR) AF: 0.000199 AC: 7 AN: 35188

Ashkenazi Jewish (ASJ) AF: 0.000208 AC: 4 AN: 19258

East Asian (EAS) AF: 0.00 AC: 0 AN: 30143

South Asian (SAS) AF: 0.000317 AC: 17 AN: 53690

European-Finnish (FIN) AF: 0.00197 AC: 80 AN: 40521

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4091

European-Non Finnish (NFE) AF: 0.00383 AC: 3165 AN: 825729

Other (OTH) AF: 0.00215 AC: 98 AN: 45517

GnomAD4 genome AF: 0.00176 AC: 197 AN: 111910 Hom.: 0 Cov.: 23 AF XY: 0.00188 AC XY: 64 AN XY: 34064

African (AFR) AF: 0.000585 AC: 18 AN: 30778

American (AMR) AF: 0.000381 AC: 4 AN: 10512

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2652

East Asian (EAS) AF: 0.00 AC: 0 AN: 3562

South Asian (SAS) AF: 0.000370 AC: 1 AN: 2702

European-Finnish (FIN) AF: 0.00116 AC: 7 AN: 6060

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 217

European-Non Finnish (NFE) AF: 0.00310 AC: 165 AN: 53207

Other (OTH) AF: 0.00130 AC: 2 AN: 1533

Alfa AF: 0.00251 Hom.: 81

Bravo AF: 0.00175

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	ARHGEF6-related disorder (1)
-	1	-	Intellectual disability, X-linked 46 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	19
DANN	Benign	0.81
PhyloP100		6.3
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.34
dbscSNV1_RF	Benign	0.31
Splicevardb		2.0
SpliceAI score (max)		0.030		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: rs140322310; hg19: chrX-135861667;