rs149918318

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS1

The NM_203447.4(DOCK8):c.452G>A(p.Arg151Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00176 in 1,614,138 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. R151R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0018 ( 9 hom. )

Consequence

DOCK8
NM_203447.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:2

Conservation

PhyloP100: 3.91

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 Likely_benign. Variant got -4 ACMG points.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00133 (203/152258) while in subpopulation NFE AF= 0.00219 (149/68024). AF 95% confidence interval is 0.0019. There are 0 homozygotes in gnomad4. There are 86 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DOCK8	NM_203447.4 linkuse as main transcript	c.452G>A	p.Arg151Gln	missense_variant	5/48	ENST00000432829.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DOCK8	ENST00000432829.7 linkuse as main transcript	c.452G>A	p.Arg151Gln	missense_variant	5/48	1	NM_203447.4		Q8NF50-1

Frequencies

GnomAD3 genomes

AF:

0.00133

AC:

203

AN:

152140

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000410

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00131

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.000377

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00219

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.00139

AC:

350

AN:

251386

Hom.:

AF XY:

0.00137

AC XY:

186

AN XY:

135870

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.000752

Gnomad ASJ exome

AF:

0.00288

Gnomad EAS exome

AF:

0.000218

Gnomad SAS exome

AF:

0.000719

Gnomad FIN exome

AF:

0.000370

Gnomad NFE exome

AF:

0.00212

Gnomad OTH exome

AF:

0.00244

GnomAD4 exome

AF:

0.00181

AC:

2643

AN:

1461880

Hom.:

Cov.:

AF XY:

0.00177

AC XY:

1288

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.000358

Gnomad4 AMR exome

AF:

0.00107

Gnomad4 ASJ exome

AF:

0.00279

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.000719

Gnomad4 FIN exome

AF:

0.000431

Gnomad4 NFE exome

AF:

0.00208

Gnomad4 OTH exome

AF:

0.00142

GnomAD4 genome

AF:

0.00133

AC:

203

AN:

152258

Hom.:

Cov.:

AF XY:

0.00116

AC XY:

AN XY:

74438

show subpopulations

Gnomad4 AFR

AF:

0.000409

Gnomad4 AMR

AF:

0.00131

Gnomad4 ASJ

AF:

0.00173

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.000377

Gnomad4 NFE

AF:

0.00219

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00209

Hom.:

Bravo

AF:

0.00143

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00156

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00221

AC:

ExAC

AF:

0.00145

AC:

176

EpiCase

AF:

0.00196

EpiControl

AF:

0.00213

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Dec 06, 2021	DNA sequence analysis of the DOCK8 gene demonstrated a sequence change, c.452G>A, in exon 5 that results in an amino acid change, p.Arg151Gln. This sequence change has been described in the gnomAD database with a frequency of 0.29% in the Ashkenazi Jewish subpopulation (dbSNP rs149918318). The p.Arg151Gln change affects a highly conserved amino acid residue located in a domain of the DOCK8 protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Arg151Gln substitution. This sequence change does not appear to have been previously described in individuals with DOCK8-related disorders. Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Arg151Gln change remains unknown at this time. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 15, 2016	The R83Q variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The NHLBI Exome Sequencing Project and the 1000 Genomes Project Consortium report R83Q was observed in 19/8600 (0.22%) and 3/694 (0.43%) alleles from individuals of European and mixed American backgrounds, respectively, indicating it may be a rare variant in these populations. The variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species; however, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -

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, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 28, 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). -

Autosomal recessive hyper-IgE syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 26, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.36

Cadd

Uncertain

Dann

Uncertain

0.99

DEOGEN2

Benign

0.088

T;.;T;.

Eigen

Uncertain

0.26

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.92

D;D;D;D

M_CAP

Benign

0.012

MetaRNN

Benign

0.0072

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.52

N;.;.;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Benign

0.44

REVEL

Benign

0.087

Sift4G

Benign

0.79

T;T;T;T

Polyphen

0.66

P;.;.;.

Vest4

0.46

MVP

0.35

MPC

0.053

ClinPred

0.019

GERP RS

6.0

Varity_R

0.071

gMVP

0.51

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.28

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.28

Position offset: -47

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