rs11789099

chr9-312134-G-A

Variant summary

Our verdict is Benign. Variant got -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:7
• Conservation: PhyloP100: 7.80

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 163173.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-312134-G-A is described in Lovd as [Benign]. Variant chr9-312134-G-A is described in Lovd as [Likely_benign].
• BA1: GnomAdExome4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0546 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DOCK8	NM_203447.4	c.709G>A	p.Glu237Lys	missense_variant	6/48	ENST00000432829.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DOCK8	ENST00000432829.7	c.709G>A	p.Glu237Lys	missense_variant	6/48	1	NM_203447.4

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

GnomAD3 exomes AF: 0.0283 AC: 7105 AN: 251142 Hom.: 159 AF XY: 0.0311 AC XY: 4228 AN XY: 135768

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 SAS exome AF: 0.0562

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

Gnomad4 AFR exome AF: 0.00636

Gnomad4 AMR exome AF: 0.0166

Gnomad4 ASJ exome AF: 0.0515

Gnomad4 EAS exome AF: 0.00108

Gnomad4 SAS exome AF: 0.0559

Gnomad4 FIN exome AF: 0.0170

Gnomad4 NFE exome AF: 0.0315

Gnomad4 OTH exome AF: 0.0288

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

Gnomad4 AFR AF: 0.00748

Gnomad4 AMR AF: 0.0251

Gnomad4 ASJ AF: 0.0495

Gnomad4 EAS AF: 0.000770

Gnomad4 SAS AF: 0.0505

Gnomad4 FIN AF: 0.0169

Gnomad4 NFE AF: 0.0313

Gnomad4 OTH AF: 0.0227

Alfa AF: 0.0306 Hom.: 166

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

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	Glu237Lys in exon 6 of DOCK8: This variant is not expected to have clinical sign ificance because it has been identified in 3.3% (283/8600) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS; dbSNP rs11789099). -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Combined immunodeficiency due to DOCK8 deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Autosomal recessive hyper-IgE syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

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;D;D
MetaRNN	Benign	0.0032	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.69	T
REVEL	Benign	0.16
Sift4G	Benign	0.51	T;T;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

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

Publications

LitVar

Other links and lift over

dbSNP: rs11789099; hg19: chr9-312134; COSMIC: COSV101210392;