rs1057515778

Variant names:

• chrX-136667904-GGAGA-G
• rs1057515778
• NM_004840.3:c.*121_*124delTCTC

Your query was ambiguous. Multiple possible variants found:

• chrX-136667904-GGAGA-G
• chrX-136667904-GGAGA-GGA
• chrX-136667904-GGAGA-GGAGAGA

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_004840.3(ARHGEF6):​c.*121_*124delTCTC variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000181 in 846,859 control chromosomes in the GnomAD database, including 1 homozygotes. There are 43 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00017 (0 hom., 6 hem., cov: 22)
  • Exomes 𝑓: 0.00018 (1 hom. 37 hem.)
• Consequence: ARHGEF6 NM_004840.3 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.327
• 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: 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: Likely_benign. The variant received -4 ACMG points.

• BS2: High AC in GnomAd4 at 19 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.*121_*124delTCTC		3_prime_UTR	Exon 22 of 22	NP_004831.1	Q15052-1
	ARHGEF6	NM_001440994.1		c.*121_*124delTCTC		3_prime_UTR	Exon 23 of 23	NP_001427923.1
	ARHGEF6	NM_001440995.1		c.*121_*124delTCTC		3_prime_UTR	Exon 22 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.*121_*124delTCTC		3_prime_UTR	Exon 22 of 22	ENSP00000250617.6	Q15052-1
	ARHGEF6	ENST00000370622.5	TSL:1	c.*121_*124delTCTC		3_prime_UTR	Exon 21 of 21	ENSP00000359656.1	Q15052-2
	ARHGEF6	ENST00000881407.1		c.*121_*124delTCTC		3_prime_UTR	Exon 23 of 23	ENSP00000551466.1

Frequencies

GnomAD3 genomes AF: 0.000174 AC: 19 AN: 108929 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00541

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000767

Gnomad OTH AF: 0.000681

GnomAD4 exome AF: 0.000182 AC: 134 AN: 737930 Hom.: 1 AF XY: 0.000183 AC XY: 37 AN XY: 202052

African (AFR) AF: 0.0000527 AC: 1 AN: 18973

American (AMR) AF: 0.000746 AC: 23 AN: 30814

Ashkenazi Jewish (ASJ) AF: 0.00417 AC: 68 AN: 16309

East Asian (EAS) AF: 0.00 AC: 0 AN: 26632

South Asian (SAS) AF: 0.00 AC: 0 AN: 43192

European-Finnish (FIN) AF: 0.0000320 AC: 1 AN: 31209

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2290

European-Non Finnish (NFE) AF: 0.0000636 AC: 34 AN: 534428

Other (OTH) AF: 0.000205 AC: 7 AN: 34083

GnomAD4 genome AF: 0.000174 AC: 19 AN: 108929 Hom.: 0 Cov.: 22 AF XY: 0.000189 AC XY: 6 AN XY: 31811

African (AFR) AF: 0.00 AC: 0 AN: 29914

American (AMR) AF: 0.00 AC: 0 AN: 10271

Ashkenazi Jewish (ASJ) AF: 0.00541 AC: 14 AN: 2588

East Asian (EAS) AF: 0.00 AC: 0 AN: 3469

South Asian (SAS) AF: 0.00 AC: 0 AN: 2491

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5649

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 235

European-Non Finnish (NFE) AF: 0.0000767 AC: 4 AN: 52180

Other (OTH) AF: 0.000681 AC: 1 AN: 1468

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000185

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Non-syndromic X-linked intellectual disability (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.33

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs1057515778; hg19: chrX-135750063;