X-136667904-GGAGA-G

Position:

• chrX-136667904-GGAGA-G

Variant summary

Our verdict is Likely benign. Variant got -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

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 Likely_benign. Variant got -4 ACMG points.

• BS2: High Hemizygotes in GnomAd4 at 6 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARHGEF6	NM_004840.3	c.*121_*124delTCTC		3_prime_UTR_variant	22/22	ENST00000250617.7	NP_004831.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARHGEF6	ENST00000250617	c.*121_*124delTCTC		3_prime_UTR_variant	22/22	1	NM_004840.3	ENSP00000250617.6
ARHGEF6	ENST00000370622.5	c.*121_*124delTCTC		3_prime_UTR_variant	21/21	1		ENSP00000359656.1
ARHGEF6	ENST00000370620.5	c.*121_*124delTCTC		3_prime_UTR_variant	21/21	2		ENSP00000359654.1

Frequencies

GnomAD3 genomes AF: 0.000174 AC: 19 AN: 108929 Hom.: 0 Cov.: 22 AF XY: 0.000189 AC XY: 6 AN XY: 31811

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

Gnomad4 AFR exome AF: 0.0000527

Gnomad4 AMR exome AF: 0.000746

Gnomad4 ASJ exome AF: 0.00417

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000320

Gnomad4 NFE exome AF: 0.0000636

Gnomad4 OTH exome AF: 0.000205

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

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00541

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000767

Gnomad4 OTH AF: 0.000681

Bravo AF: 0.000185

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Non-syndromic X-linked intellectual disability Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs1057515778; hg19: chrX-135750063;