chr9-286593-C-A

Position:

chr9-286593-C-A

Variant summary

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

The NM_203447.4(DOCK8):c.289C>A(p.Pro97Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.5 in 1,613,234 control chromosomes in the GnomAD database, including 204,070 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.48 ( 18265 hom., cov: 32)

Exomes 𝑓: 0.50 ( 185805 hom. )

Consequence

DOCK8
NM_203447.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11O:1

Conservation

PhyloP100: 3.24

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=3.5923292E-6).

BP6

Variant 9-286593-C-A is Benign according to our data. Variant chr9-286593-C-A is described in ClinVar as [Benign]. Clinvar id is 178766.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-286593-C-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.715 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DOCK8	NM_203447.4 linkuse as main transcript	c.289C>A	p.Pro97Thr	missense_variant	3/48	ENST00000432829.7	NP_982272.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DOCK8	ENST00000432829.7 linkuse as main transcript	c.289C>A	p.Pro97Thr	missense_variant	3/48	1	NM_203447.4	ENSP00000394888		Q8NF50-1

Frequencies

GnomAD3 genomes

AF:

0.485

AC:

73595

AN:

151746

Hom.:

18252

Cov.:

show subpopulations

Gnomad AFR

AF:

0.405

Gnomad AMI

AF:

0.260

Gnomad AMR

AF:

0.519

Gnomad ASJ

AF:

0.476

Gnomad EAS

AF:

0.735

Gnomad SAS

AF:

0.559

Gnomad FIN

AF:

0.572

Gnomad MID

AF:

0.513

Gnomad NFE

AF:

0.490

Gnomad OTH

AF:

0.515

GnomAD3 exomes

AF:

0.525

AC:

132036

AN:

251288

Hom.:

35528

AF XY:

0.525

AC XY:

71366

AN XY:

135818

show subpopulations

Gnomad AFR exome

AF:

0.403

Gnomad AMR exome

AF:

0.543

Gnomad ASJ exome

AF:

0.470

Gnomad EAS exome

AF:

0.746

Gnomad SAS exome

AF:

0.545

Gnomad FIN exome

AF:

0.567

Gnomad NFE exome

AF:

0.493

Gnomad OTH exome

AF:

0.534

GnomAD4 exome

AF:

0.501

AC:

732667

AN:

1461370

Hom.:

185805

Cov.:

AF XY:

0.503

AC XY:

365670

AN XY:

726998

show subpopulations

Gnomad4 AFR exome

AF:

0.402

Gnomad4 AMR exome

AF:

0.540

Gnomad4 ASJ exome

AF:

0.469

Gnomad4 EAS exome

AF:

0.743

Gnomad4 SAS exome

AF:

0.545

Gnomad4 FIN exome

AF:

0.563

Gnomad4 NFE exome

AF:

0.488

Gnomad4 OTH exome

AF:

0.508

GnomAD4 genome

AF:

0.485

AC:

73636

AN:

151864

Hom.:

18265

Cov.:

AF XY:

0.492

AC XY:

36526

AN XY:

74206

show subpopulations

Gnomad4 AFR

AF:

0.404

Gnomad4 AMR

AF:

0.519

Gnomad4 ASJ

AF:

0.476

Gnomad4 EAS

AF:

0.735

Gnomad4 SAS

AF:

0.560

Gnomad4 FIN

AF:

0.572

Gnomad4 NFE

AF:

0.491

Gnomad4 OTH

AF:

0.520

Alfa

AF:

0.486

Hom.:

42459

Bravo

AF:

0.478

TwinsUK

AF:

0.480

AC:

1779

ALSPAC

AF:

0.487

AC:

1875

ESP6500AA

AF:

0.414

AC:

1825

ESP6500EA

AF:

0.490

AC:

4213

ExAC

AF:

0.520

AC:

63186

Asia WGS

AF:

0.650

AC:

2260

AN:

3478

EpiCase

AF:

0.489

EpiControl

AF:

0.482

ClinVar

Significance: Benign

Submissions summary: Benign:11Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	Pro97Thr in exon 3 of DOCK8: This variant is not expected to have clinical signi ficance because it has been identified in 49.0% (4213/8600) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs529208). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Nov 12, 2023	This variant is classified as Benign based on local population frequency. This variant was detected in 80% of patients studied by a panel of primary immunodeficiencies. Number of patients: 77. Only high quality variants are reported. -

Combined immunodeficiency due to DOCK8 deficiency

Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -
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. -
Benign, criteria provided, single submitter	clinical testing	Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust	Aug 25, 2015	- -

not provided

Benign:2Other:1

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	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. -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Autosomal recessive hyper-IgE syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.094

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.32

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.40

T;T;.;T;.

Eigen

Uncertain

0.34

Eigen_PC

Uncertain

0.31

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.75

T;T;T;T;T

MetaRNN

Benign

0.0000036

T;T;T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Uncertain

2.4

M;.;.;.;.

MutationTaster

Benign

0.0088

P;P;P

PrimateAI

Uncertain

0.49

PROVEAN

Pathogenic

-5.5

.;D;.;D;D

REVEL

Benign

0.20

Sift

Benign

0.052

.;T;.;T;D

Sift4G

Uncertain

0.010

D;T;D;T;D

Polyphen

0.58

P;.;.;.;.

Vest4

0.23

MPC

0.16

ClinPred

0.048

GERP RS

4.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.30

gMVP

0.46

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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