rs183417070

Variant names:

• chrX-136747501-G-A
• rs183417070
• NM_004840.3:c.334+7C>T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_004840.3(ARHGEF6):​c.334+7C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000504 in 1,201,508 control chromosomes in the GnomAD database, including 2 homozygotes. There are 169 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0024 (1 hom., 58 hem., cov: 20)
  • Exomes 𝑓: 0.00031 (1 hom. 111 hem.)
• Consequence: ARHGEF6 NM_004840.3 splice_region, intron
• Scores: Splicing: ADA: 0.00006595
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.139
• 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: Orphanet, ClinGen, Illumina
• 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: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant X-136747501-G-A is Benign according to our data. Variant chrX-136747501-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 445824.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 261 XL,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGEF6	NM_004840.3	c.334+7C>T		splice_region_variant, intron_variant	Intron 3 of 21	ENST00000250617.7	NP_004831.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARHGEF6	ENST00000250617.7	c.334+7C>T		splice_region_variant, intron_variant	Intron 3 of 21	1	NM_004840.3	ENSP00000250617.6
ARHGEF6	ENST00000370622.5	c.-129+7C>T		splice_region_variant, intron_variant	Intron 2 of 20	1		ENSP00000359656.1
ARHGEF6	ENST00000370620.5	c.-129+7C>T		splice_region_variant, intron_variant	Intron 2 of 20	2		ENSP00000359654.1

Frequencies

GnomAD3 genomes AF: 0.00235 AC: 255 AN: 108478 Hom.: 1 Cov.: 20

Gnomad AFR AF: 0.00800

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000496

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000402

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000172

Gnomad OTH AF: 0.00206

GnomAD2 exomes AF: 0.000747 AC: 137 AN: 183300 AF XY: 0.000531

Gnomad AFR exome AF: 0.00806

Gnomad AMR exome AF: 0.000401

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000171

Gnomad OTH exome AF: 0.000442

GnomAD4 exome AF: 0.000315 AC: 344 AN: 1092980 Hom.: 1 Cov.: 29 AF XY: 0.000310 AC XY: 111 AN XY: 358628

African (AFR) AF: 0.00745 AC: 196 AN: 26307

American (AMR) AF: 0.000512 AC: 18 AN: 35187

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19340

East Asian (EAS) AF: 0.00 AC: 0 AN: 30177

South Asian (SAS) AF: 0.000148 AC: 8 AN: 54040

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40449

Middle Eastern (MID) AF: 0.000728 AC: 3 AN: 4121

European-Non Finnish (NFE) AF: 0.000115 AC: 96 AN: 837428

Other (OTH) AF: 0.000501 AC: 23 AN: 45931

GnomAD4 genome AF: 0.00240 AC: 261 AN: 108528 Hom.: 1 Cov.: 20 AF XY: 0.00188 AC XY: 58 AN XY: 30922

African (AFR) AF: 0.00818 AC: 243 AN: 29696

American (AMR) AF: 0.000495 AC: 5 AN: 10097

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2610

East Asian (EAS) AF: 0.00 AC: 0 AN: 3445

South Asian (SAS) AF: 0.000403 AC: 1 AN: 2479

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 212

European-Non Finnish (NFE) AF: 0.000172 AC: 9 AN: 52424

Other (OTH) AF: 0.00204 AC: 3 AN: 1473

Alfa AF: 0.00104 Hom.: 3

Bravo AF: 0.00246

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 04, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.71
DANN	Benign	0.73
PhyloP100		0.14
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000066
dbscSNV1_RF	Benign	0.0060
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

dbSNP: rs183417070; hg19: chrX-135829660;