chr9-407040-G-GGCTTGGCT

Variant names:

• chr9-407040-G-GGCTTGGCT
• rs886037645
• NM_203447.4:c.3504_3505insTGGCTGCT

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_203447.4(DOCK8):​c.3504_3505insTGGCTGCT​(p.Ala1169TrpfsTer28) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DOCK8 NM_203447.4 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 3.62
• Publications: 0 publications found

Genes affected

DOCK8 (HGNC:19191): (dedicator of cytokinesis 8) This gene encodes a member of the DOCK180 family of guanine nucleotide exchange factors. Guanine nucleotide exchange factors interact with Rho GTPases and are components of intracellular signaling networks. Mutations in this gene result in the autosomal recessive form of the hyper-IgE syndrome. Alternatively spliced transcript variants encoding different isoforms have been described.[provided by RefSeq, Jun 2010]

DOCK8 Gene-Disease associations (from GenCC):

• combined immunodeficiency due to DOCK8 deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: Orphanet, ClinGen, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, Genomics England PanelApp
• autosomal dominant non-syndromic intellectual disability

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• complex neurodevelopmental disorder

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-407040-G-GGCTTGGCT is Pathogenic according to our data. Variant chr9-407040-G-GGCTTGGCT is described in ClinVar as Pathogenic. ClinVar VariationId is 60563.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_203447.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DOCK8	NM_203447.4	MANE Select	c.3504_3505insTGGCTGCT	p.Ala1169TrpfsTer28	frameshift	Exon 28 of 48	NP_982272.2
	DOCK8	NM_001193536.2		c.3300_3301insTGGCTGCT	p.Ala1101TrpfsTer28	frameshift	Exon 27 of 47	NP_001180465.1
	DOCK8	NM_001190458.2		c.3204_3205insTGGCTGCT	p.Ala1069TrpfsTer28	frameshift	Exon 26 of 46	NP_001177387.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DOCK8	ENST00000432829.7	TSL:1 MANE Select	c.3504_3505insTGGCTGCT	p.Ala1169TrpfsTer28	frameshift	Exon 28 of 48	ENSP00000394888.3
	DOCK8	ENST00000469391.5	TSL:1	c.3204_3205insTGGCTGCT	p.Ala1069TrpfsTer28	frameshift	Exon 26 of 46	ENSP00000419438.1
	DOCK8	ENST00000382329.2	TSL:1	c.3204_3205insTGGCTGCT	p.Ala1069TrpfsTer28	frameshift	Exon 27 of 46	ENSP00000371766.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Combined immunodeficiency due to DOCK8 deficiency Pathogenic:1

Nov 19, 2009

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.6
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs886037645; hg19: chr9-407040;