rs149768069

Positions:

• chrX-136747580-C-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_004840.3(ARHGEF6):​c.262G>C​(p.Asp88His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000184 in 1,186,180 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 82 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00019 (0 hom., 9 hem., cov: 20)
  • Exomes 𝑓: 0.00018 (0 hom. 73 hem.)
• Consequence: ARHGEF6 NM_004840.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 1.15

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 Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.016631484).
• BP6: Variant X-136747580-C-G is Benign according to our data. Variant chrX-136747580-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 210252.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}. Variant chrX-136747580-C-G is described in Lovd as [Likely_benign].
• BS2: High Hemizygotes in GnomAd4 at 9 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARHGEF6	NM_004840.3	c.262G>C	p.Asp88His	missense_variant	3/22	ENST00000250617.7	NP_004831.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARHGEF6	ENST00000250617.7	c.262G>C	p.Asp88His	missense_variant	3/22	1	NM_004840.3	ENSP00000250617.6
ARHGEF6	ENST00000370622.5	c.-201G>C		5_prime_UTR_variant	2/21	1		ENSP00000359656.1
ARHGEF6	ENST00000370620.5	c.-201G>C		5_prime_UTR_variant	2/21	2		ENSP00000359654.1

Frequencies

GnomAD3 genomes AF: 0.000191 AC: 20 AN: 104819 Hom.: 0 Cov.: 20 AF XY: 0.000316 AC XY: 9 AN XY: 28491

Gnomad AFR AF: 0.000106

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000107

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000864

Gnomad FIN AF: 0.00182

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000773

Gnomad OTH AF: 0.000728

GnomAD3 exomes AF: 0.000355 AC: 65 AN: 183099 Hom.: 0 AF XY: 0.000459 AC XY: 31 AN XY: 67603

Gnomad AFR exome AF: 0.000152

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000315

Gnomad FIN exome AF: 0.00234

Gnomad NFE exome AF: 0.000208

Gnomad OTH exome AF: 0.000663

GnomAD4 exome AF: 0.000183 AC: 198 AN: 1081322 Hom.: 0 Cov.: 29 AF XY: 0.000209 AC XY: 73 AN XY: 348734

Gnomad4 AFR exome AF: 0.0000769

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000297

Gnomad4 FIN exome AF: 0.00249

Gnomad4 NFE exome AF: 0.0000760

Gnomad4 OTH exome AF: 0.000243

GnomAD4 genome AF: 0.000191 AC: 20 AN: 104858 Hom.: 0 Cov.: 20 AF XY: 0.000315 AC XY: 9 AN XY: 28540

Gnomad4 AFR AF: 0.000106

Gnomad4 AMR AF: 0.000107

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000868

Gnomad4 FIN AF: 0.00182

Gnomad4 NFE AF: 0.0000773

Gnomad4 OTH AF: 0.000719

Alfa AF: 0.000194 Hom.: 5

Bravo AF: 0.000121

ESP6500AA AF: 0.000261 AC: 1

ESP6500EA AF: 0.000297 AC: 2

ExAC AF: 0.000428 AC: 52

EpiCase AF: 0.000436

EpiControl AF: 0.000297

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Aug 04, 2015

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 02, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	21
DANN	Benign	0.96
DEOGEN2	Benign	0.41	T
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.053	D
MetaRNN	Benign	0.017	T
MetaSVM	Uncertain	-0.24	T
MutationAssessor	Benign	-0.23	N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.30	N
REVEL	Benign	0.23
Sift	Benign	0.23	T
Sift4G	Benign	0.29	T
Polyphen		0.0	B
Vest4		0.054
MVP		0.79
MPC		0.33
ClinPred		0.029	T
GERP RS		3.6
Varity_R		0.26
gMVP		0.42

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs149768069; hg19: chrX-135829739;