NM_004840.3:c.2138G>A

Variant names:

• chrX-136669534-C-T
• NM_004840.3:c.2138G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_004840.3(ARHGEF6):​c.2138G>A​(p.Ser713Asn) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000824 in 1,092,046 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes in GnomAD. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0000082 (0 hom. 4 hem.)
• Consequence: ARHGEF6 NM_004840.3 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.93
• 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: Likely_benign. The variant received -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 9 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.2138G>A	p.Ser713Asn	missense splice_region	Exon 21 of 22	NP_004831.1	Q15052-1
	ARHGEF6	NM_001440994.1		c.2219G>A	p.Ser740Asn	missense splice_region	Exon 22 of 23	NP_001427923.1
	ARHGEF6	NM_001440995.1		c.2150G>A	p.Ser717Asn	missense splice_region	Exon 21 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.2138G>A	p.Ser713Asn	missense splice_region	Exon 21 of 22	ENSP00000250617.6	Q15052-1
	ARHGEF6	ENST00000370622.5	TSL:1	c.1676G>A	p.Ser559Asn	missense splice_region	Exon 20 of 21	ENSP00000359656.1	Q15052-2
	ARHGEF6	ENST00000881407.1		c.2219G>A	p.Ser740Asn	missense splice_region	Exon 22 of 23	ENSP00000551466.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 0.00000824 AC: 9 AN: 1092046 Hom.: 0 Cov.: 28 AF XY: 0.0000112 AC XY: 4 AN XY: 357646

African (AFR) AF: 0.00 AC: 0 AN: 26300

American (AMR) AF: 0.00 AC: 0 AN: 35191

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19324

East Asian (EAS) AF: 0.00 AC: 0 AN: 30168

South Asian (SAS) AF: 0.00 AC: 0 AN: 53966

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40499

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4119

European-Non Finnish (NFE) AF: 0.00000837 AC: 7 AN: 836603

Other (OTH) AF: 0.0000436 AC: 2 AN: 45876

GnomAD4 genome Cov.: 22

EpiCase AF: 0.0000545

EpiControl AF: 0.00

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	Pathogenic	0.69
BayesDel_addAF	Benign	-0.064	T
BayesDel_noAF	Benign	-0.33
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.47	T
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.27	D
MetaRNN	Uncertain	0.70	D
MetaSVM	Uncertain	0.036	D
MutationAssessor	Uncertain	2.9	M
PhyloP100		6.9
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.19
Sift	Uncertain	0.0060	D
Sift4G	Benign	0.12	T
Polyphen		1.0	D
Vest4		0.84
MutPred		0.22		Loss of sheet (P = 0.0181)
MVP		0.89
MPC		0.71
ClinPred		0.95	D
GERP RS		5.7
Varity_R		0.74
gMVP		0.53
Mutation Taster		=47/53	disease causing

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

hg19: chrX-135751693;