rs3209441

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_203447.4(DOCK8):c.187G>A(p.Asp63Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.158 in 1,613,776 control chromosomes in the GnomAD database, including 22,346 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.11 ( 1334 hom., cov: 32)

Exomes 𝑓: 0.16 ( 21012 hom. )

Consequence

DOCK8
NM_203447.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7O:1

Conservation

PhyloP100: 9.60

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.001942724).

BP6

Variant 9-286491-G-A is Benign according to our data. Variant chr9-286491-G-A is described in ClinVar as [Benign]. Clinvar id is 137156.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.174 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DOCK8	NM_203447.4 link	c.187G>A	p.Asp63Asn	missense_variant	Exon 3 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.187G>A	p.Asp63Asn	missense_variant	Exon 3 of 48	1	NM_203447.4	ENSP00000394888.3		Q8NF50-1

Frequencies

GnomAD3 genomes

AF:

0.114

AC:

17388

AN:

152094

Hom.:

1335

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0306

Gnomad AMI

AF:

0.268

Gnomad AMR

AF:

0.0980

Gnomad ASJ

AF:

0.0991

Gnomad EAS

AF:

0.00269

Gnomad SAS

AF:

0.116

Gnomad FIN

AF:

0.111

Gnomad MID

AF:

0.120

Gnomad NFE

AF:

0.177

Gnomad OTH

AF:

0.114

GnomAD3 exomes

AF:

0.122

AC:

30733

AN:

251134

Hom.:

2372

AF XY:

0.128

AC XY:

17433

AN XY:

135696

show subpopulations

Gnomad AFR exome

AF:

0.0279

Gnomad AMR exome

AF:

0.0701

Gnomad ASJ exome

AF:

0.112

Gnomad EAS exome

AF:

0.00141

Gnomad SAS exome

AF:

0.120

Gnomad FIN exome

AF:

0.118

Gnomad NFE exome

AF:

0.173

Gnomad OTH exome

AF:

0.132

GnomAD4 exome

AF:

0.163

AC:

237665

AN:

1461564

Hom.:

21012

Cov.:

AF XY:

0.162

AC XY:

117891

AN XY:

727078

show subpopulations

Gnomad4 AFR exome

AF:

0.0251

Gnomad4 AMR exome

AF:

0.0734

Gnomad4 ASJ exome

AF:

0.116

Gnomad4 EAS exome

AF:

0.000706

Gnomad4 SAS exome

AF:

0.119

Gnomad4 FIN exome

AF:

0.120

Gnomad4 NFE exome

AF:

0.184

Gnomad4 OTH exome

AF:

0.144

GnomAD4 genome

AF:

0.114

AC:

17378

AN:

152212

Hom.:

1334

Cov.:

AF XY:

0.110

AC XY:

8180

AN XY:

74412

show subpopulations

Gnomad4 AFR

AF:

0.0305

Gnomad4 AMR

AF:

0.0978

Gnomad4 ASJ

AF:

0.0991

Gnomad4 EAS

AF:

0.00270

Gnomad4 SAS

AF:

0.116

Gnomad4 FIN

AF:

0.111

Gnomad4 NFE

AF:

0.177

Gnomad4 OTH

AF:

0.113

Alfa

AF:

0.162

Hom.:

5261

Bravo

AF:

0.109

TwinsUK

AF:

0.189

AC:

700

ALSPAC

AF:

0.186

AC:

716

ESP6500AA

AF:

0.0315

AC:

139

ESP6500EA

AF:

0.176

AC:

1513

ExAC

AF:

0.123

AC:

14953

Asia WGS

AF:

0.0480

AC:

169

AN:

3478

EpiCase

AF:

0.173

EpiControl

AF:

0.184

ClinVar

Significance: Benign

Submissions summary: Benign:7Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 22% of patients studied by a panel of primary immunodeficiencies. Number of patients: 21. Only high quality variants are reported. -

Feb 21, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Asp63Asn in exon 3 of DOCK8: This variant is not expected to have clinical signi ficance because it has been identified in 17.6% (1513/8600) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs3209441). -

Mar 11, 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. -

not provided

Benign:1Other:1

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpreted as Benign and reported on 04-27-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. This variant was reported in an individual referred for clinical diagnostic genetic testing. -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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. -

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

0.26

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.36

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.69

Eigen

Pathogenic

0.87

Eigen_PC

Pathogenic

0.85

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

MetaRNN

Benign

0.0019

MetaSVM

Benign

-1.2

MutationAssessor

Uncertain

2.5

PrimateAI

Uncertain

0.62

Sift4G

Uncertain

0.0020

Polyphen

1.0

Vest4

0.30

ClinPred

0.014

GERP RS

5.5

Varity_R

0.95

gMVP

0.71

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over