rs913703

Positions:

• chr9-370244-A-G

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_203447.4(DOCK8):​c.1812A>G​(p.Lys604=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.234 in 1,611,044 control chromosomes in the GnomAD database, including 45,786 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (4279 hom., cov: 32)
  • Exomes 𝑓: 0.23 (41507 hom.)
• Consequence: DOCK8 NM_203447.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8 O:1
• Conservation: PhyloP100: 0.763

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 9-370244-A-G is Benign according to our data. Variant chr9-370244-A-G is described in ClinVar as [Benign]. Clinvar id is 137137.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-370244-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.763 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.259 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DOCK8	NM_203447.4	c.1812A>G	p.Lys604=	synonymous_variant	16/48	ENST00000432829.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DOCK8	ENST00000432829.7	c.1812A>G	p.Lys604=	synonymous_variant	16/48	1	NM_203447.4

Frequencies

GnomAD3 genomes AF: 0.233 AC: 35477 AN: 152036 Hom.: 4269 Cov.: 32

Gnomad AFR AF: 0.263

Gnomad AMI AF: 0.329

Gnomad AMR AF: 0.220

Gnomad ASJ AF: 0.188

Gnomad EAS AF: 0.0730

Gnomad SAS AF: 0.251

Gnomad FIN AF: 0.177

Gnomad MID AF: 0.301

Gnomad NFE AF: 0.239

Gnomad OTH AF: 0.234

GnomAD3 exomes AF: 0.217 AC: 54557 AN: 251342 Hom.: 6426 AF XY: 0.221 AC XY: 30028 AN XY: 135842

Gnomad AFR exome AF: 0.272

Gnomad AMR exome AF: 0.193

Gnomad ASJ exome AF: 0.207

Gnomad EAS exome AF: 0.0646

Gnomad SAS exome AF: 0.256

Gnomad FIN exome AF: 0.179

Gnomad NFE exome AF: 0.239

Gnomad OTH exome AF: 0.222

GnomAD4 exome AF: 0.234 AC: 341983 AN: 1458890 Hom.: 41507 Cov.: 32 AF XY: 0.236 AC XY: 171044 AN XY: 725966

Gnomad4 AFR exome AF: 0.271

Gnomad4 AMR exome AF: 0.197

Gnomad4 ASJ exome AF: 0.203

Gnomad4 EAS exome AF: 0.0791

Gnomad4 SAS exome AF: 0.255

Gnomad4 FIN exome AF: 0.180

Gnomad4 NFE exome AF: 0.242

Gnomad4 OTH exome AF: 0.238

GnomAD4 genome AF: 0.233 AC: 35509 AN: 152154 Hom.: 4279 Cov.: 32 AF XY: 0.230 AC XY: 17094 AN XY: 74362

Gnomad4 AFR AF: 0.263

Gnomad4 AMR AF: 0.219

Gnomad4 ASJ AF: 0.188

Gnomad4 EAS AF: 0.0732

Gnomad4 SAS AF: 0.252

Gnomad4 FIN AF: 0.177

Gnomad4 NFE AF: 0.239

Gnomad4 OTH AF: 0.232

Alfa AF: 0.236 Hom.: 8603

Bravo AF: 0.238

Asia WGS AF: 0.164 AC: 571 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 27, 2013	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, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	Lys604Lys in exon 16 of DOCK8: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue and is not located wit hin the splice consensus sequence. It has been identified in 26.9% (1184/4406) o f African American chromosomes from a broad population by the NHLBI Exome Sequen cing Project (http://evs.gs.washington.edu/EVS; dbSNP rs913703). -
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 40% of patients studied by a panel of primary immunodeficiencies. Number of patients: 38. Only high quality variants are reported. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Combined immunodeficiency due to DOCK8 deficiency Benign:1

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. -

Autosomal recessive hyper-IgE syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 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
BayesDel_noAF	Benign	-0.43
CADD	Benign	7.8
DANN	Benign	0.89
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8

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: rs913703; hg19: chr9-370244; COSMIC: COSV66619880;