rs10970979

Positions:

Variant summary

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

The NM_203447.4(DOCK8):c.1238A>G(p.Asn413Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.284 in 1,613,726 control chromosomes in the GnomAD database, including 67,987 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.26 ( 5110 hom., cov: 32)

Exomes 𝑓: 0.29 ( 62877 hom. )

Consequence

DOCK8
NM_203447.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8O:1

Conservation

PhyloP100: -0.00800

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=9.584427E-4).

BP6

Variant 9-334337-A-G is Benign according to our data. Variant chr9-334337-A-G is described in ClinVar as [Benign]. Clinvar id is 163174.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-334337-A-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.3 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.1238A>G	p.Asn413Ser	missense_variant	11/48	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.1238A>G	p.Asn413Ser	missense_variant	11/48	1	NM_203447.4	ENSP00000394888		Q8NF50-1

Frequencies

GnomAD3 genomes

AF:

0.256

AC:

38838

AN:

151950

Hom.:

5106

Cov.:

show subpopulations

Gnomad AFR

AF:

0.225

Gnomad AMI

AF:

0.339

Gnomad AMR

AF:

0.212

Gnomad ASJ

AF:

0.325

Gnomad EAS

AF:

0.0328

Gnomad SAS

AF:

0.257

Gnomad FIN

AF:

0.208

Gnomad MID

AF:

0.332

Gnomad NFE

AF:

0.303

Gnomad OTH

AF:

0.271

GnomAD3 exomes

AF:

0.245

AC:

61474

AN:

251170

Hom.:

8478

AF XY:

0.252

AC XY:

34160

AN XY:

135734

show subpopulations

Gnomad AFR exome

AF:

0.219

Gnomad AMR exome

AF:

0.153

Gnomad ASJ exome

AF:

0.333

Gnomad EAS exome

AF:

0.0319

Gnomad SAS exome

AF:

0.262

Gnomad FIN exome

AF:

0.217

Gnomad NFE exome

AF:

0.303

Gnomad OTH exome

AF:

0.266

GnomAD4 exome

AF:

0.287

AC:

419275

AN:

1461658

Hom.:

62877

Cov.:

AF XY:

0.287

AC XY:

208450

AN XY:

727122

show subpopulations

Gnomad4 AFR exome

AF:

0.215

Gnomad4 AMR exome

AF:

0.158

Gnomad4 ASJ exome

AF:

0.332

Gnomad4 EAS exome

AF:

0.0288

Gnomad4 SAS exome

AF:

0.258

Gnomad4 FIN exome

AF:

0.220

Gnomad4 NFE exome

AF:

0.308

Gnomad4 OTH exome

AF:

0.278

GnomAD4 genome

AF:

0.255

AC:

38849

AN:

152068

Hom.:

5110

Cov.:

AF XY:

0.249

AC XY:

18505

AN XY:

74330

show subpopulations

Gnomad4 AFR

AF:

0.224

Gnomad4 AMR

AF:

0.211

Gnomad4 ASJ

AF:

0.325

Gnomad4 EAS

AF:

0.0331

Gnomad4 SAS

AF:

0.258

Gnomad4 FIN

AF:

0.208

Gnomad4 NFE

AF:

0.303

Gnomad4 OTH

AF:

0.267

Alfa

AF:

0.289

Hom.:

15882

Bravo

AF:

0.252

ESP6500AA

AF:

0.229

AC:

1009

ESP6500EA

AF:

0.309

AC:

2659

ExAC

AF:

0.249

AC:

30196

Asia WGS

AF:

0.135

AC:

472

AN:

3476

EpiCase

AF:

0.308

EpiControl

AF:

0.313

ClinVar

Significance: Benign

Submissions summary: Benign:8Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	Asn413Ser in exon 11 of DOCK8: This variant is not expected to have clinical sig nificance because it has been identified in 30.9% (2659/8600) of European Americ an chromosomes from a broad population by the NHLBI Exome Sequencing Project (ht tp://evs.gs.washington.edu/EVS; dbSNP rs10970979). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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 34% of patients studied by a panel of primary immunodeficiencies. Number of patients: 33. Only high quality variants are reported. -

not provided

Benign:2Other:1

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
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. -

Combined immunodeficiency due to DOCK8 deficiency

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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	Genome-Nilou Lab	Jul 14, 2021	- -

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

0.051

BayesDel_addAF

Benign

-0.76

BayesDel_noAF

Benign

-0.72

CADD

Benign

1.2

DANN

Benign

0.90

DEOGEN2

Benign

0.087

T;.;.

Eigen

Benign

-0.90

Eigen_PC

Benign

-0.71

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.75

T;T;T

MetaRNN

Benign

0.00096

T;T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

0.33

N;.;.

MutationTaster

Benign

0.029

P;P;P

PrimateAI

Benign

0.38

PROVEAN

Benign

-0.88

.;.;N

REVEL

Benign

0.056

Sift

Benign

0.44

.;.;T

Sift4G

Benign

0.64

T;T;T

Polyphen

0.0

B;.;.

Vest4

0.031

MPC

0.037

ClinPred

0.0034

GERP RS

2.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.023

gMVP

0.089

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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