NM_004840.3:c.1994C>G

Variant names:

• chrX-136675048-G-C
• NM_004840.3:c.1994C>G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_004840.3(ARHGEF6):​c.1994C>G​(p.Ala665Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: ARHGEF6 NM_004840.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.17

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.777

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGEF6	NM_004840.3	c.1994C>G	p.Ala665Gly	missense_variant	Exon 19 of 22	ENST00000250617.7	NP_004831.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARHGEF6	ENST00000250617.7	c.1994C>G	p.Ala665Gly	missense_variant	Exon 19 of 22	1	NM_004840.3	ENSP00000250617.6
ARHGEF6	ENST00000370622.5	c.1532C>G	p.Ala511Gly	missense_variant	Exon 18 of 21	1		ENSP00000359656.1
ARHGEF6	ENST00000370620.5	c.1532C>G	p.Ala511Gly	missense_variant	Exon 18 of 21	2		ENSP00000359654.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 22

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 16, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1994C>G (p.A665G) alteration is located in exon 19 (coding exon 19) of the ARHGEF6 gene. This alteration results from a C to G substitution at nucleotide position 1994, causing the alanine (A) at amino acid position 665 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.61	.;.;D
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	.;D;D
M_CAP	Pathogenic	0.67	D
MetaRNN	Pathogenic	0.78	D;D;D
MetaSVM	Benign	-0.65	T
MutationAssessor	Benign	1.9	.;.;M
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-2.5	D;D;D
REVEL	Uncertain	0.40
Sift	Benign	0.037	D;D;T
Sift4G	Benign	0.18	T;T;T
Polyphen		1.0	.;.;D
Vest4		0.57
MutPred		0.76		.;.;Loss of stability (P = 0.0584);
MVP		0.88
MPC		0.95
ClinPred		0.94	D
GERP RS		5.6
Varity_R		0.66
gMVP		0.38

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-135757207;