ARHGEF6 p.His314His

Variant names:

• chrX-136707011-T-T
• NM_004840.3:c.

Your query was ambiguous. Multiple possible variants found:

• chrX-136707012--
• chrX-136707012-G-A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_004840.3(ARHGEF6):​c. variant causes a exon region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 22)
• Consequence: ARHGEF6 NM_004840.3 exon_region
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.93
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.		exon_region	Exon 9 of 22	NP_004831.1	Q15052-1
	ARHGEF6	NM_001440994.1		c.		exon_region	Exon 10 of 23	NP_001427923.1
	ARHGEF6	NM_001440995.1		c.		exon_region	Exon 9 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.		exon_region	Exon 9 of 22	ENSP00000250617.6	Q15052-1
	ARHGEF6	ENST00000370622.5	TSL:1	c.		exon_region	Exon 8 of 21	ENSP00000359656.1	Q15052-2
	ARHGEF6	ENST00000881407.1		c.		exon_region	Exon 10 of 23	ENSP00000551466.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 22

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.9

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chrX-135789170;