rs149768069

Variant names:

• chrX-136747580-C-G
• rs149768069
• NM_004840.3:c.262G>C

Variant summary

Our verdict is Benign. The variant received -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. 16/21 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
• 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: G2P, Labcorp Genetics (formerly Invitae)
• X-linked intellectual disability

  Inheritance: XL Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 210252.
• BS2: High AC in GnomAd4 at 20 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.262G>C	p.Asp88His	missense	Exon 3 of 22	NP_004831.1	Q15052-1
	ARHGEF6	NM_001440994.1		c.262G>C	p.Asp88His	missense	Exon 3 of 23	NP_001427923.1
	ARHGEF6	NM_001440995.1		c.262G>C	p.Asp88His	missense	Exon 3 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.262G>C	p.Asp88His	missense	Exon 3 of 22	ENSP00000250617.6	Q15052-1
	ARHGEF6	ENST00000370622.5	TSL:1	c.-201G>C		5_prime_UTR	Exon 2 of 21	ENSP00000359656.1	Q15052-2
	ARHGEF6	ENST00000881407.1		c.262G>C	p.Asp88His	missense	Exon 3 of 23	ENSP00000551466.1

Frequencies

GnomAD3 genomes AF: 0.000191 AC: 20 AN: 104819 Hom.: 0 Cov.: 20

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

GnomAD2 exomes AF: 0.000355 AC: 65 AN: 183099 AF XY: 0.000459

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 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

African (AFR) AF: 0.0000769 AC: 2 AN: 26015

American (AMR) AF: 0.00 AC: 0 AN: 34989

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19071

East Asian (EAS) AF: 0.00 AC: 0 AN: 29751

South Asian (SAS) AF: 0.000297 AC: 16 AN: 53811

European-Finnish (FIN) AF: 0.00249 AC: 99 AN: 39837

Middle Eastern (MID) AF: 0.00172 AC: 7 AN: 4080

European-Non Finnish (NFE) AF: 0.0000760 AC: 63 AN: 828424

Other (OTH) AF: 0.000243 AC: 11 AN: 45344

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

African (AFR) AF: 0.000106 AC: 3 AN: 28306

American (AMR) AF: 0.000107 AC: 1 AN: 9379

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2591

East Asian (EAS) AF: 0.00 AC: 0 AN: 3322

South Asian (SAS) AF: 0.000868 AC: 2 AN: 2303

European-Finnish (FIN) AF: 0.00182 AC: 9 AN: 4955

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 201

European-Non Finnish (NFE) AF: 0.0000773 AC: 4 AN: 51734

Other (OTH) AF: 0.000719 AC: 1 AN: 1391

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

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		1.1
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
Mutation Taster		=89/11	polymorphism

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

Other links and lift over

dbSNP: rs149768069; hg19: chrX-135829739;