rs3209441

chr9-286491-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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 (★★). Synonymous variant affecting the same amino acid position (i.e. D63D) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.11 (1334 hom., cov: 32)
  • Exomes 𝑓: 0.16 (21012 hom.)
• Consequence: DOCK8 NM_203447.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6 O:1
• Conservation: PhyloP100: 9.60

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]

ACMG classification

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/exons	MANE	UniProt
DOCK8	NM_203447.4	c.187G>A	p.Asp63Asn	missense_variant	3/48	ENST00000432829.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DOCK8	ENST00000432829.7	c.187G>A	p.Asp63Asn	missense_variant	3/48	1	NM_203447.4

Frequencies

GnomAD3 genomes AF: 0.114 AC: 17388 AN: 152094 Hom.: 1335 Cov.: 32

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

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.: 31 AF XY: 0.162 AC XY: 117891 AN XY: 727078

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.: 32 AF XY: 0.110 AC XY: 8180 AN XY: 74412

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:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	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). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 11, 2014	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. -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jan 24, 2024	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. -

Combined immunodeficiency due to DOCK8 deficiency Benign:1

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. -

Autosomal recessive hyper-IgE syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

not provided Other:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.36
Cadd	Pathogenic	28
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.69	D
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
MetaRNN	Benign	0.0019	T
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.5	M
MutationTaster	Benign	3.5e-8	P;P;P
PrimateAI	Uncertain	0.62	T
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.30
ClinPred		0.014	T
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

Other links and lift over

dbSNP: rs3209441; hg19: chr9-286491; COSMIC: COSV66634213;