chrX-136690714-C-A

Variant names:

• chrX-136690714-C-A
• rs779277722
• NM_004840.3:c.1081G>T

Variant summary

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

The NM_004840.3(ARHGEF6):​c.1081G>T​(p.Ala361Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A361T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0000018 (0 hom. 2 hem.)
  • Failed GnomAD Quality Control
• Consequence: ARHGEF6 NM_004840.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.91
• Publications: 1 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.1081G>T	p.Ala361Ser	missense	Exon 10 of 22	NP_004831.1	Q15052-1
	ARHGEF6	NM_001440994.1		c.1162G>T	p.Ala388Ser	missense	Exon 11 of 23	NP_001427923.1
	ARHGEF6	NM_001440995.1		c.1081G>T	p.Ala361Ser	missense	Exon 10 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.1081G>T	p.Ala361Ser	missense	Exon 10 of 22	ENSP00000250617.6	Q15052-1
	ARHGEF6	ENST00000370622.5	TSL:1	c.619G>T	p.Ala207Ser	missense	Exon 9 of 21	ENSP00000359656.1	Q15052-2
	ARHGEF6	ENST00000881407.1		c.1162G>T	p.Ala388Ser	missense	Exon 11 of 23	ENSP00000551466.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000182 AC: 2 AN: 1097525 Hom.: 0 Cov.: 29 AF XY: 0.00000551 AC XY: 2 AN XY: 362903

African (AFR) AF: 0.00 AC: 0 AN: 26385

American (AMR) AF: 0.0000284 AC: 1 AN: 35198

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19382

East Asian (EAS) AF: 0.00 AC: 0 AN: 30199

South Asian (SAS) AF: 0.00 AC: 0 AN: 54123

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40527

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4134

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 841506

Other (OTH) AF: 0.00 AC: 0 AN: 46071

GnomAD4 genome Cov.: 22

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Uncertain	0.038	T
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.57	D
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.55	D
MetaRNN	Uncertain	0.59	D
MetaSVM	Uncertain	0.050	D
MutationAssessor	Uncertain	2.7	M
PhyloP100		7.9
PrimateAI	Benign	0.40	T
PROVEAN	Uncertain	-2.9	D
REVEL	Uncertain	0.34
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.018	D
Polyphen		0.96	D
Vest4		0.45
MutPred		0.52		Gain of disorder (P = 0.0212)
MVP		0.83
MPC		0.81
ClinPred		0.98	D
GERP RS		5.9
Varity_R		0.83
gMVP		0.28
Mutation Taster		=32/68	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs779277722; hg19: chrX-135772873;