X-136672075-C-T

Position:

• chrX-136672075-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_004840.3(ARHGEF6):​c.2080G>A​(p.Glu694Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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: 5.23

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 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARHGEF6	NM_004840.3	c.2080G>A	p.Glu694Lys	missense_variant	20/22	ENST00000250617.7	NP_004831.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARHGEF6	ENST00000250617.7	c.2080G>A	p.Glu694Lys	missense_variant	20/22	1	NM_004840.3	ENSP00000250617.6
ARHGEF6	ENST00000370622.5	c.1618G>A	p.Glu540Lys	missense_variant	19/21	1		ENSP00000359656.1
ARHGEF6	ENST00000370620.5	c.1618G>A	p.Glu540Lys	missense_variant	19/21	2		ENSP00000359654.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 22

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Vanishing white matter disease Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

Dec 12, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Benign	-0.064	T
BayesDel_noAF	Benign	-0.33
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.46	.;.;T
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	1.0	.;D;D
M_CAP	Pathogenic	0.54	D
MetaRNN	Uncertain	0.74	D;D;D
MetaSVM	Benign	-0.56	T
MutationAssessor	Uncertain	2.5	.;.;M
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-2.0	N;N;N
REVEL	Benign	0.14
Sift	Uncertain	0.024	D;D;D
Sift4G	Benign	0.089	T;T;T
Polyphen		0.74	.;.;P
Vest4		0.61
MutPred		0.46		.;.;Gain of methylation at E694 (P = 0.0071);
MVP		0.81
MPC		0.60
ClinPred		0.96	D
GERP RS		5.2
Varity_R		0.58
gMVP		0.65

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

LitVar

Other links and lift over

dbSNP: rs2076230593; hg19: chrX-135754234;