X-118496045-C-CT

Variant names:

• chrX-118496045-C-CT
• NM_144658.4:c.75dupT

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_144658.4(DOCK11):​c.75dupT​(p.Glu26fs) variant causes a frameshift, stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: DOCK11 NM_144658.4 frameshift, stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 0.231
• Publications: 0 publications found

Genes affected

DOCK11 (HGNC:23483): (dedicator of cytokinesis 11) Predicted to enable guanyl-nucleotide exchange factor activity. Predicted to be involved in several processes, including marginal zone B cell differentiation; positive regulation of GTPase activity; and positive regulation of filopodium assembly. Predicted to be located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

DOCK11 Gene-Disease associations (from GenCC):

• autoinflammatory disease, multisystem, with immune dysregulation, X-linked

  Inheritance: XL Classification: STRONG, LIMITED Submitted by: Ambry Genetics, ClinGen

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 10 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-118496045-C-CT is Pathogenic according to our data. Variant chrX-118496045-C-CT is described in ClinVar as Pathogenic. ClinVar VariationId is 2444466.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_144658.4. 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
	DOCK11	NM_144658.4	MANE Select	c.75dupT	p.Glu26fs	frameshift stop_gained	Exon 1 of 53	NP_653259.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DOCK11	ENST00000276202.9	TSL:1 MANE Select	c.75dupT	p.Glu26fs	frameshift stop_gained	Exon 1 of 53	ENSP00000276202.7	Q5JSL3
	DOCK11	ENST00000276204.10	TSL:5	c.75dupT	p.Glu26fs	frameshift stop_gained	Exon 1 of 53	ENSP00000276204.6	A6NIW2
	DOCK11	ENST00000966546.1		c.75dupT	p.Glu26fs	frameshift stop_gained	Exon 1 of 53	ENSP00000636605.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 23

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Autoinflammatory disease, multisystem, with immune dysregulation, X-linked (1)
1	-	-	Inborn error of hematopoiesis and immunity with systemic inflammation and normocytic anemia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.23

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

hg19: chrX-117630008;