chrX-136667904-G-GGA

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_004840.3(ARHGEF6):​c.*123_*124dupTC variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000189 in 845,797 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000018 (0 hom., 1 hem., cov: 22)
  • Exomes 𝑓: 0.00021 (0 hom. 1 hem.)
• Consequence: ARHGEF6 NM_004840.3 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.44
• 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: Uncertain_significance. The variant received 0 ACMG points.

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_*124dupTC		3_prime_UTR	Exon 22 of 22	NP_004831.1	Q15052-1
	ARHGEF6	NM_001440994.1		c.*123_*124dupTC		3_prime_UTR	Exon 23 of 23	NP_001427923.1
	ARHGEF6	NM_001440995.1		c.*123_*124dupTC		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_*124dupTC		3_prime_UTR	Exon 22 of 22	ENSP00000250617.6	Q15052-1
	ARHGEF6	ENST00000370622.5	TSL:1	c.*123_*124dupTC		3_prime_UTR	Exon 21 of 21	ENSP00000359656.1	Q15052-2
	ARHGEF6	ENST00000881407.1		c.*123_*124dupTC		3_prime_UTR	Exon 23 of 23	ENSP00000551466.1

Frequencies

GnomAD3 genomes AF: 0.0000184 AC: 2 AN: 108922 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000288

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000192

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000214 AC: 158 AN: 736875 Hom.: 0 Cov.: 11 AF XY: 0.00000496 AC XY: 1 AN XY: 201617

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

African (AFR) AF: 0.000158 AC: 3 AN: 18951

American (AMR) AF: 0.00 AC: 0 AN: 30788

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16299

East Asian (EAS) AF: 0.0000376 AC: 1 AN: 26605

South Asian (SAS) AF: 0.000139 AC: 6 AN: 43150

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2284

European-Non Finnish (NFE) AF: 0.000261 AC: 139 AN: 533563

Other (OTH) AF: 0.000235 AC: 8 AN: 34026

⚠️ 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: 0.0000184 AC: 2 AN: 108922 Hom.: 0 Cov.: 22 AF XY: 0.0000314 AC XY: 1 AN XY: 31806

African (AFR) AF: 0.00 AC: 0 AN: 29909

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

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

East Asian (EAS) AF: 0.000288 AC: 1 AN: 3469

South Asian (SAS) AF: 0.00 AC: 0 AN: 2490

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5648

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

European-Non Finnish (NFE) AF: 0.0000192 AC: 1 AN: 52180

Other (OTH) AF: 0.00 AC: 0 AN: 1468

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-2.4

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1057515778; hg19: chrX-135750063;