rs139391329

Positions:

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The ENST00000432829.7(DOCK8):c.663C>A(p.Asp221Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00235 in 1,614,224 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0017 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0024 ( 9 hom. )

Consequence

DOCK8
ENST00000432829.7 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: 1.64

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004763007).

BP6

Variant 9-312088-C-A is Benign according to our data. Variant chr9-312088-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 366546.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1, Likely_benign=2}. Variant chr9-312088-C-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00169 (257/152340) while in subpopulation NFE AF= 0.00281 (191/68032). AF 95% confidence interval is 0.00248. There are 0 homozygotes in gnomad4. There are 123 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DOCK8	NM_203447.4 linkuse as main transcript	c.663C>A	p.Asp221Glu	missense_variant	6/48	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.663C>A	p.Asp221Glu	missense_variant	6/48	1	NM_203447.4	ENSP00000394888		Q8NF50-1

Frequencies

GnomAD3 genomes

AF:

0.00169

AC:

257

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000748

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00207

Gnomad FIN

AF:

0.00179

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00281

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.00175

AC:

440

AN:

251414

Hom.:

AF XY:

0.00183

AC XY:

248

AN XY:

135876

show subpopulations

Gnomad AFR exome

AF:

0.000738

Gnomad AMR exome

AF:

0.000463

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00252

Gnomad FIN exome

AF:

0.00139

Gnomad NFE exome

AF:

0.00255

Gnomad OTH exome

AF:

0.00212

GnomAD4 exome

AF:

0.00242

AC:

3542

AN:

1461884

Hom.:

Cov.:

AF XY:

0.00241

AC XY:

1750

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.000418

Gnomad4 AMR exome

AF:

0.000402

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00279

Gnomad4 FIN exome

AF:

0.00129

Gnomad4 NFE exome

AF:

0.00279

Gnomad4 OTH exome

AF:

0.00139

GnomAD4 genome

AF:

0.00169

AC:

257

AN:

152340

Hom.:

Cov.:

AF XY:

0.00165

AC XY:

123

AN XY:

74488

show subpopulations

Gnomad4 AFR

AF:

0.000746

Gnomad4 AMR

AF:

0.000261

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00207

Gnomad4 FIN

AF:

0.00179

Gnomad4 NFE

AF:

0.00281

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.00227

Hom.:

Bravo

AF:

0.00144

TwinsUK

AF:

0.00593

AC:

ALSPAC

AF:

0.00337

AC:

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.00291

AC:

ExAC

AF:

0.00173

AC:

210

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00218

EpiControl

AF:

0.00124

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	DOCK8: BP4, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 10, 2019	- -

Combined immunodeficiency due to DOCK8 deficiency

Uncertain:1

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

DOCK8-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 31, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Intellectual disability

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Jan 01, 2019

- -

Autosomal recessive hyper-IgE syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 25, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.54

CADD

Benign

DANN

Benign

0.29

DEOGEN2

Benign

0.10

T;.;.

Eigen

Benign

-0.92

Eigen_PC

Benign

-0.68

FATHMM_MKL

Uncertain

0.81

LIST_S2

Benign

0.71

T;T;T

M_CAP

Benign

0.0042

MetaRNN

Benign

0.0048

T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

-0.93

N;.;.

MutationTaster

Benign

0.76

D;N;N

PrimateAI

Benign

0.43

PROVEAN

Benign

0.99

.;N;N

REVEL

Benign

0.057

Sift

Benign

1.0

.;T;T

Sift4G

Benign

1.0

T;T;T

Polyphen

0.0

B;.;.

Vest4

0.16

MutPred

0.20

Gain of helix (P = 0.0225);.;.;

MVP

0.20

MPC

0.042

ClinPred

0.0056

GERP RS

2.8

Varity_R

0.069

gMVP

0.23

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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