X-136667904-GGAGA-GGA

Variant names:

• chrX-136667904-GGA-G
• rs1057515778
• NM_004840.3:c.*123_*124delTC

Variant summary

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

The NM_004840.3(ARHGEF6):​c.*123_*124delTC variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00373 in 799,056 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000055 (0 hom., 1 hem., cov: 22)
  • Exomes 𝑓: 0.0043 (0 hom. 1 hem.)
• Consequence: ARHGEF6 NM_004840.3 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0330
• 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 6 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.*123_*124delTC		3_prime_UTR	Exon 22 of 22	NP_004831.1	Q15052-1
	ARHGEF6	NM_001440994.1		c.*123_*124delTC		3_prime_UTR	Exon 23 of 23	NP_001427923.1
	ARHGEF6	NM_001440995.1		c.*123_*124delTC		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.*123_*124delTC		3_prime_UTR	Exon 22 of 22	ENSP00000250617.6	Q15052-1
	ARHGEF6	ENST00000370622.5	TSL:1	c.*123_*124delTC		3_prime_UTR	Exon 21 of 21	ENSP00000359656.1	Q15052-2
	ARHGEF6	ENST00000881407.1		c.*123_*124delTC		3_prime_UTR	Exon 23 of 23	ENSP00000551466.1

Frequencies

GnomAD3 genomes AF: 0.0000551 AC: 6 AN: 108897 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.000167

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000974

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00431 AC: 2972 AN: 690123 Hom.: 0 AF XY: 0.00000541 AC XY: 1 AN XY: 184705

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00438 AC: 77 AN: 17576

American (AMR) AF: 0.00300 AC: 84 AN: 28013

Ashkenazi Jewish (ASJ) AF: 0.00309 AC: 46 AN: 14892

East Asian (EAS) AF: 0.00277 AC: 67 AN: 24229

South Asian (SAS) AF: 0.00171 AC: 67 AN: 39281

European-Finnish (FIN) AF: 0.00340 AC: 98 AN: 28846

Middle Eastern (MID) AF: 0.00188 AC: 4 AN: 2129

European-Non Finnish (NFE) AF: 0.00478 AC: 2405 AN: 503599

Other (OTH) AF: 0.00393 AC: 124 AN: 31558

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000551 AC: 6 AN: 108933 Hom.: 0 Cov.: 22 AF XY: 0.0000314 AC XY: 1 AN XY: 31837

African (AFR) AF: 0.000167 AC: 5 AN: 29970

American (AMR) AF: 0.0000973 AC: 1 AN: 10279

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2588

East Asian (EAS) AF: 0.00 AC: 0 AN: 3457

South Asian (SAS) AF: 0.00 AC: 0 AN: 2480

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5637

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 214

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 52156

Other (OTH) AF: 0.00 AC: 0 AN: 1488

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.033
Mutation Taster		=100/0	polymorphism

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; COSMIC: COSV51688937;