9-289590-CTTT-CTT

Variant names:

• chr9-289590-CT-C
• rs727505303
• NM_203447.4:c.404+16delT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_203447.4(DOCK8):​c.404+16delT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0322 in 1,607,164 control chromosomes in the GnomAD database, including 1,012 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.031 (96 hom., cov: 32)
  • Exomes 𝑓: 0.032 (916 hom.)
• Consequence: DOCK8 NM_203447.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.667
• Publications: 1 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: Ambry Genetics, Genomics England PanelApp, ClinGen, Orphanet, Labcorp Genetics (formerly Invitae), G2P
• 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: Benign. The variant received -16 ACMG points.

• BP6: Variant 9-289590-CT-C is Benign according to our data. Variant chr9-289590-CT-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 180037.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0529 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DOCK8	NM_203447.4	MANE Select	c.404+16delT		intron	N/A	NP_982272.2	Q8NF50-1
	DOCK8	NM_001193536.2		c.200+16delT		intron	N/A	NP_001180465.1	Q8NF50-3
	DOCK8	NM_001190458.2		c.200+16delT		intron	N/A	NP_001177387.1	Q8NF50-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DOCK8	ENST00000432829.7	TSL:1 MANE Select	c.404+16delT		intron	N/A	ENSP00000394888.3	Q8NF50-1
	DOCK8	ENST00000469391.5	TSL:1	c.200+16delT		intron	N/A	ENSP00000419438.1	Q8NF50-4
	DOCK8	ENST00000382329.2	TSL:1	c.200+16delT		intron	N/A	ENSP00000371766.2	A2A369

Frequencies

GnomAD3 genomes AF: 0.0306 AC: 4647 AN: 152092 Hom.: 96 Cov.: 32

Gnomad AFR AF: 0.0280

Gnomad AMI AF: 0.138

Gnomad AMR AF: 0.0251

Gnomad ASJ AF: 0.0660

Gnomad EAS AF: 0.000769

Gnomad SAS AF: 0.0588

Gnomad FIN AF: 0.0154

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0328

Gnomad OTH AF: 0.0273

GnomAD2 exomes AF: 0.0320 AC: 7986 AN: 249946 AF XY: 0.0345

Gnomad AFR exome AF: 0.0301

Gnomad AMR exome AF: 0.0159

Gnomad ASJ exome AF: 0.0652

Gnomad EAS exome AF: 0.000549

Gnomad FIN exome AF: 0.0159

Gnomad NFE exome AF: 0.0337

Gnomad OTH exome AF: 0.0303

GnomAD4 exome AF: 0.0324 AC: 47176 AN: 1454954 Hom.: 916 Cov.: 30 AF XY: 0.0338 AC XY: 24453 AN XY: 723590

African (AFR) AF: 0.0286 AC: 953 AN: 33334

American (AMR) AF: 0.0157 AC: 702 AN: 44586

Ashkenazi Jewish (ASJ) AF: 0.0623 AC: 1622 AN: 26042

East Asian (EAS) AF: 0.000202 AC: 8 AN: 39546

South Asian (SAS) AF: 0.0626 AC: 5302 AN: 84702

European-Finnish (FIN) AF: 0.0165 AC: 876 AN: 53118

Middle Eastern (MID) AF: 0.0411 AC: 217 AN: 5284

European-Non Finnish (NFE) AF: 0.0322 AC: 35679 AN: 1108328

Other (OTH) AF: 0.0303 AC: 1817 AN: 60014

GnomAD4 genome AF: 0.0306 AC: 4655 AN: 152210 Hom.: 96 Cov.: 32 AF XY: 0.0304 AC XY: 2262 AN XY: 74436

African (AFR) AF: 0.0282 AC: 1173 AN: 41534

American (AMR) AF: 0.0250 AC: 383 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0660 AC: 229 AN: 3470

East Asian (EAS) AF: 0.000771 AC: 4 AN: 5188

South Asian (SAS) AF: 0.0585 AC: 282 AN: 4824

European-Finnish (FIN) AF: 0.0154 AC: 163 AN: 10602

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.0328 AC: 2229 AN: 67984

Other (OTH) AF: 0.0270 AC: 57 AN: 2112

Alfa AF: 0.0196 Hom.: 13

Bravo AF: 0.0298

Asia WGS AF: 0.0210 AC: 73 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	1	Hyper-IgE syndrome (1)
-	-	1	not provided (1)
-	-	1	Not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.67
Mutation Taster		=100/0	polymorphism (auto)

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: rs727505303; hg19: chr9-289590;