rs73382631

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_203447.4(DOCK8):c.3208A>G(p.Asn1070Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0062 in 1,613,616 control chromosomes in the GnomAD database, including 476 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N1070S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.030 ( 224 hom., cov: 32)

Exomes 𝑓: 0.0037 ( 252 hom. )

Consequence

DOCK8
NM_203447.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 2.30

Publications

3 publications found

Variant links:

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

DOCK8 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0033479035).

BP6

Variant 9-399233-A-G is Benign according to our data. Variant chr9-399233-A-G is described in ClinVar as [Benign]. Clinvar id is 137143.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.101 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DOCK8	NM_203447.4 link	c.3208A>G	p.Asn1070Asp	missense_variant	Exon 26 of 48	ENST00000432829.7	NP_982272.2	Q8NF50-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DOCK8	ENST00000432829.7 link	c.3208A>G	p.Asn1070Asp	missense_variant	Exon 26 of 48	1	NM_203447.4	ENSP00000394888.3		Q8NF50-1

Frequencies

GnomAD3 genomes

AF:

0.0302

AC:

4588

AN:

151822

Hom.:

223

Cov.:

show subpopulations

Gnomad AFR

AF:

0.104

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0150

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.000603

Gnomad OTH

AF:

0.0192

GnomAD2 exomes

AF:

0.00837

AC:

2101

AN:

251048

AF XY:

0.00612

show subpopulations

Gnomad AFR exome

AF:

0.110

Gnomad AMR exome

AF:

0.00503

Gnomad ASJ exome

AF:

0.00149

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000741

Gnomad OTH exome

AF:

0.00473

GnomAD4 exome

AF:

0.00369

AC:

5389

AN:

1461678

Hom.:

252

Cov.:

AF XY:

0.00326

AC XY:

2368

AN XY:

727118

show subpopulations

African (AFR)

AF:

0.114

AC:

3808

AN:

33468

American (AMR)

AF:

0.00662

AC:

296

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00134

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.000394

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.0000563

AC:

AN:

53302

Middle Eastern (MID)

AF:

0.0172

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.000508

AC:

565

AN:

1111948

Other (OTH)

AF:

0.00909

AC:

549

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

257

514

770

1027

1284

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0304

AC:

4612

AN:

151938

Hom.:

224

Cov.:

AF XY:

0.0292

AC XY:

2167

AN XY:

74326

show subpopulations

African (AFR)

AF:

0.104

AC:

4292

AN:

41304

American (AMR)

AF:

0.0150

AC:

229

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00115

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.000208

AC:

AN:

4808

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10592

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000603

AC:

AN:

67996

Other (OTH)

AF:

0.0190

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

204

408

613

817

1021

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0240

Hom.:

167

Bravo

AF:

0.0363

ESP6500AA

AF:

0.106

AC:

468

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0102

AC:

1243

Asia WGS

AF:

0.0130

AC:

AN:

3478

EpiCase

AF:

0.000545

EpiControl

AF:

0.00107

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Mar 20, 2014

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Feb 21, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Asn1070Asp in exon 26 of DOCK8: This variant is not expected to have clinical si gnificance because it has been identified in 10.6% (468/4404) of African America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs73382631). -

Combined immunodeficiency due to DOCK8 deficiency

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.55

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.15

T;.;.;T;T

Eigen

Benign

-0.029

Eigen_PC

Benign

0.16

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.94

D;D;D;T;D

MetaRNN

Benign

0.0033

T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.4

M;.;.;.;.

PhyloP100

2.3

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-1.2

.;.;N;N;N

REVEL

Benign

0.10

Sift

Benign

0.093

.;.;T;T;T

Sift4G

Benign

0.31

T;T;T;T;T

Polyphen

0.0

B;.;.;B;B

Vest4

0.44

MPC

0.051

ClinPred

0.018

GERP RS

6.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.14

gMVP

0.43

Mutation Taster

=94/6

polymorphism (auto)

(source)

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

Publications

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rs73382631

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over