chrX-136681971-A-G

Variant names:

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

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.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
• 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: 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=-0.71).
• BP6: Variant X-136681971-A-G is Benign according to our data. Variant chrX-136681971-A-G is described in ClinVar as Benign. ClinVar VariationId is 128448.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 462 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.1480-3T>C		splice_region intron	N/A	NP_004831.1	Q15052-1
	ARHGEF6	NM_001440994.1		c.1561-3T>C		splice_region intron	N/A	NP_001427923.1
	ARHGEF6	NM_001440995.1		c.1480-3T>C		splice_region intron	N/A	NP_001427924.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGEF6	ENST00000250617.7	TSL:1 MANE Select	c.1480-3T>C		splice_region intron	N/A	ENSP00000250617.6	Q15052-1
	ARHGEF6	ENST00000370622.5	TSL:1	c.1018-3T>C		splice_region intron	N/A	ENSP00000359656.1	Q15052-2
	ARHGEF6	ENST00000881407.1		c.1561-3T>C		splice_region intron	N/A	ENSP00000551466.1

Frequencies

GnomAD3 genomes AF: 0.00413 AC: 462 AN: 111978 Hom.: 2 Cov.: 23

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

GnomAD2 exomes AF: 0.00136 AC: 249 AN: 183031 AF XY: 0.000977

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 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

African (AFR) AF: 0.0151 AC: 393 AN: 25981

American (AMR) AF: 0.00117 AC: 41 AN: 35164

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19228

East Asian (EAS) AF: 0.00 AC: 0 AN: 30094

South Asian (SAS) AF: 0.0000373 AC: 2 AN: 53646

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40270

Middle Eastern (MID) AF: 0.00221 AC: 9 AN: 4073

European-Non Finnish (NFE) AF: 0.000159 AC: 131 AN: 822285

Other (OTH) AF: 0.00143 AC: 65 AN: 45389

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

African (AFR) AF: 0.0138 AC: 425 AN: 30884

American (AMR) AF: 0.00132 AC: 14 AN: 10569

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2644

East Asian (EAS) AF: 0.00 AC: 0 AN: 3604

South Asian (SAS) AF: 0.00 AC: 0 AN: 2695

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6064

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 216

European-Non Finnish (NFE) AF: 0.000263 AC: 14 AN: 53144

Other (OTH) AF: 0.00590 AC: 9 AN: 1525

Alfa AF: 0.00223 Hom.: 8

Bravo AF: 0.00494

EpiCase AF: 0.000273

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	ARHGEF6-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	4.5
DANN	Benign	0.72
PhyloP100		0.56
Mutation Taster		=96/4	polymorphism (auto)

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

Other links and lift over

dbSNP: rs138342895; hg19: chrX-135764130;