rs138342895

Variant names:

• chrX-136681971-A-G
• rs138342895
• NM_004840.3:c.1480-3T>C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_004840.3(ARHGEF6):​c.1480-3T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000928 in 1,188,161 control chromosomes in the GnomAD database, including 5 homozygotes. There are 305 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0041 (2 hom., 114 hem., cov: 23)
  • Exomes 𝑓: 0.00060 (3 hom. 191 hem.)
• Consequence: ARHGEF6 NM_004840.3 splice_region, intron
• Scores: Splicing: ADA: 0.0002239
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.558

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant X-136681971-A-G is Benign according to our data. Variant chrX-136681971-A-G is described in ClinVar as [Benign]. Clinvar id is 128448.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-136681971-A-G is described in Lovd as [Benign].
• BS2: High Homozygotes in GnomAd4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGEF6	NM_004840.3	c.1480-3T>C		splice_region_variant, intron_variant	Intron 13 of 21	ENST00000250617.7	NP_004831.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARHGEF6	ENST00000250617.7	c.1480-3T>C		splice_region_variant, intron_variant	Intron 13 of 21	1	NM_004840.3	ENSP00000250617.6
ARHGEF6	ENST00000370622.5	c.1018-3T>C		splice_region_variant, intron_variant	Intron 12 of 20	1		ENSP00000359656.1
ARHGEF6	ENST00000370620.5	c.1018-3T>C		splice_region_variant, intron_variant	Intron 12 of 20	2		ENSP00000359654.1

Frequencies

GnomAD3 genomes AF: 0.00413 AC: 462 AN: 111978 Hom.: 2 Cov.: 23 AF XY: 0.00337 AC XY: 115 AN XY: 34154

Gnomad AFR AF: 0.0138

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00133

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000263

Gnomad OTH AF: 0.00598

GnomAD3 exomes AF: 0.00136 AC: 249 AN: 183031 Hom.: 1 AF XY: 0.000977 AC XY: 66 AN XY: 67569

Gnomad AFR exome AF: 0.0147

Gnomad AMR exome AF: 0.00131

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000524

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000208

Gnomad OTH exome AF: 0.000443

GnomAD4 exome AF: 0.000596 AC: 641 AN: 1076130 Hom.: 3 Cov.: 26 AF XY: 0.000556 AC XY: 191 AN XY: 343224

Gnomad4 AFR exome AF: 0.0151

Gnomad4 AMR exome AF: 0.00117

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000373

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000159

Gnomad4 OTH exome AF: 0.00143

GnomAD4 genome AF: 0.00412 AC: 462 AN: 112031 Hom.: 2 Cov.: 23 AF XY: 0.00333 AC XY: 114 AN XY: 34217

Gnomad4 AFR AF: 0.0138

Gnomad4 AMR AF: 0.00132

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000263

Gnomad4 OTH AF: 0.00590

Alfa AF: 0.00223 Hom.: 8

Bravo AF: 0.00494

EpiCase AF: 0.000273

EpiControl AF: 0.000237

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

Jul 08, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

ARHGEF6-related disorder Benign:1

Aug 24, 2024

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	4.5
DANN	Benign	0.72

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00022
dbscSNV1_RF	Benign	0.028
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: rs138342895; hg19: chrX-135764130;