chrX-136667826-AAAC-A

Variant names:

• chrX-136667826-AAAC-A
• rs770569536
• NM_004840.3:c.*200_*202delGTT

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP6_Moderate BS2

The NM_004840.3(ARHGEF6):​c.*200_*202delGTT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000429 in 485,350 control chromosomes in the GnomAD database, including 1 homozygotes. There are 63 hemizygotes in GnomAD. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., 11 hem., cov: 22)
  • Exomes 𝑓: 0.00048 (1 hom. 52 hem.)
• Consequence: ARHGEF6 NM_004840.3 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.07
• 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: Likely_benign. The variant received -6 ACMG points.

• BP6: Variant X-136667826-AAAC-A is Benign according to our data. Variant chrX-136667826-AAAC-A is described in ClinVar as Likely_benign. ClinVar VariationId is 367934.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 29 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.*200_*202delGTT		3_prime_UTR	Exon 22 of 22	NP_004831.1	Q15052-1
	ARHGEF6	NM_001440994.1		c.*200_*202delGTT		3_prime_UTR	Exon 23 of 23	NP_001427923.1
	ARHGEF6	NM_001440995.1		c.*200_*202delGTT		3_prime_UTR	Exon 22 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.*200_*202delGTT		3_prime_UTR	Exon 22 of 22	ENSP00000250617.6	Q15052-1
	ARHGEF6	ENST00000370622.5	TSL:1	c.*200_*202delGTT		3_prime_UTR	Exon 21 of 21	ENSP00000359656.1	Q15052-2
	ARHGEF6	ENST00000881407.1		c.*200_*202delGTT		3_prime_UTR	Exon 23 of 23	ENSP00000551466.1

Frequencies

GnomAD3 genomes AF: 0.000250 AC: 28 AN: 111895 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00753

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000664

GnomAD4 exome AF: 0.000479 AC: 179 AN: 373400 Hom.: 1 AF XY: 0.000471 AC XY: 52 AN XY: 110410

African (AFR) AF: 0.00 AC: 0 AN: 10468

American (AMR) AF: 0.00 AC: 0 AN: 15196

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 10476

East Asian (EAS) AF: 0.00768 AC: 175 AN: 22799

South Asian (SAS) AF: 0.0000386 AC: 1 AN: 25916

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 23117

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1456

European-Non Finnish (NFE) AF: 0.00000412 AC: 1 AN: 242771

Other (OTH) AF: 0.0000943 AC: 2 AN: 21201

GnomAD4 genome AF: 0.000259 AC: 29 AN: 111950 Hom.: 0 Cov.: 22 AF XY: 0.000322 AC XY: 11 AN XY: 34126

African (AFR) AF: 0.00 AC: 0 AN: 30793

American (AMR) AF: 0.00 AC: 0 AN: 10604

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2655

East Asian (EAS) AF: 0.00784 AC: 28 AN: 3573

South Asian (SAS) AF: 0.00 AC: 0 AN: 2642

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6136

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 219

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53121

Other (OTH) AF: 0.000656 AC: 1 AN: 1524

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000431

Asia WGS AF: 0.000398 AC: 1 AN: 2522

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Non-syndromic X-linked intellectual disability (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.1

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

Other links and lift over

dbSNP: rs770569536; hg19: chrX-135749985;