rs11789099

Variant names:

• chr9-312134-G-A
• rs11789099
• NM_203447.4:c.709G>A

Your query was ambiguous. Multiple possible variants found:

• chr9-312134-G-A
• chr9-312134-G-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_203447.4(DOCK8):​c.709G>A​(p.Glu237Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0301 in 1,614,184 control chromosomes in the GnomAD database, including 905 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.023 (73 hom., cov: 33)
  • Exomes 𝑓: 0.031 (832 hom.)
• Consequence: DOCK8 NM_203447.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 7.80
• Publications: 16 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0031790435).
• BP6: Variant 9-312134-G-A is Benign according to our data. Variant chr9-312134-G-A is described in ClinVar as Benign. ClinVar VariationId is 163173.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0546 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.709G>A	p.Glu237Lys	missense	Exon 6 of 48	NP_982272.2	Q8NF50-1
	DOCK8	NM_001193536.2		c.505G>A	p.Glu169Lys	missense	Exon 5 of 47	NP_001180465.1	Q8NF50-3
	DOCK8	NM_001190458.2		c.505G>A	p.Glu169Lys	missense	Exon 5 of 46	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.709G>A	p.Glu237Lys	missense	Exon 6 of 48	ENSP00000394888.3	Q8NF50-1
	DOCK8	ENST00000469391.5	TSL:1	c.505G>A	p.Glu169Lys	missense	Exon 5 of 46	ENSP00000419438.1	Q8NF50-4
	DOCK8	ENST00000382329.2	TSL:1	c.505G>A	p.Glu169Lys	missense	Exon 6 of 46	ENSP00000371766.2	A2A369

Frequencies

GnomAD3 genomes AF: 0.0235 AC: 3571 AN: 152218 Hom.: 73 Cov.: 33

Gnomad AFR AF: 0.00745

Gnomad AMI AF: 0.0976

Gnomad AMR AF: 0.0251

Gnomad ASJ AF: 0.0495

Gnomad EAS AF: 0.000768

Gnomad SAS AF: 0.0513

Gnomad FIN AF: 0.0169

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0313

Gnomad OTH AF: 0.0229

GnomAD2 exomes AF: 0.0283 AC: 7105 AN: 251142 AF XY: 0.0311

Gnomad AFR exome AF: 0.00689

Gnomad AMR exome AF: 0.0169

Gnomad ASJ exome AF: 0.0530

Gnomad EAS exome AF: 0.000762

Gnomad FIN exome AF: 0.0174

Gnomad NFE exome AF: 0.0314

Gnomad OTH exome AF: 0.0330

GnomAD4 exome AF: 0.0308 AC: 45086 AN: 1461848 Hom.: 832 Cov.: 32 AF XY: 0.0321 AC XY: 23311 AN XY: 727226

African (AFR) AF: 0.00636 AC: 213 AN: 33480

American (AMR) AF: 0.0166 AC: 743 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0515 AC: 1345 AN: 26134

East Asian (EAS) AF: 0.00108 AC: 43 AN: 39700

South Asian (SAS) AF: 0.0559 AC: 4821 AN: 86248

European-Finnish (FIN) AF: 0.0170 AC: 906 AN: 53420

Middle Eastern (MID) AF: 0.0404 AC: 233 AN: 5768

European-Non Finnish (NFE) AF: 0.0315 AC: 35042 AN: 1111982

Other (OTH) AF: 0.0288 AC: 1740 AN: 60394

GnomAD4 genome AF: 0.0234 AC: 3567 AN: 152336 Hom.: 73 Cov.: 33 AF XY: 0.0232 AC XY: 1732 AN XY: 74502

African (AFR) AF: 0.00748 AC: 311 AN: 41572

American (AMR) AF: 0.0251 AC: 384 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0495 AC: 172 AN: 3472

East Asian (EAS) AF: 0.000770 AC: 4 AN: 5194

South Asian (SAS) AF: 0.0505 AC: 244 AN: 4830

European-Finnish (FIN) AF: 0.0169 AC: 180 AN: 10620

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0313 AC: 2130 AN: 68024

Other (OTH) AF: 0.0227 AC: 48 AN: 2116

Alfa AF: 0.0292 Hom.: 317

Bravo AF: 0.0227

TwinsUK AF: 0.0289 AC: 107

ALSPAC AF: 0.0343 AC: 132

ESP6500AA AF: 0.00817 AC: 36

ESP6500EA AF: 0.0329 AC: 283

ExAC AF: 0.0287 AC: 3484

Asia WGS AF: 0.0170 AC: 59 AN: 3478

EpiCase AF: 0.0345

EpiControl AF: 0.0331

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (3)
-	-	1	Combined immunodeficiency due to DOCK8 deficiency (1)
-	-	1	Not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.36
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.97	D
MetaRNN	Benign	0.0032	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L
PhyloP100		7.8
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.16
Sift	Benign	0.54	T
Sift4G	Benign	0.51	T
Polyphen		0.78	P
Vest4		0.28
MPC		0.19
ClinPred		0.014	T
GERP RS		5.6
Varity_R		0.32
gMVP		0.49
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs11789099; hg19: chr9-312134; COSMIC: COSV101210392;