rs1887957

chr9-441952-G-Achr9-441952-G-Cchr9-441952-G-T

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.5433G>A(p.Glu1811=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.813 in 1,613,816 control chromosomes in the GnomAD database, including 536,424 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.76 (45203 hom., cov: 31)
  • Exomes 𝑓: 0.82 (491221 hom.)
• Consequence: DOCK8 NM_203447.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10 O:1
• Conservation: PhyloP100: 0.269

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 9-441952-G-A is Benign according to our data. Variant chr9-441952-G-A is described in ClinVar as [Benign]. Clinvar id is 178771.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-441952-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.269 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.972 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DOCK8	NM_203447.4	c.5433G>A	p.Glu1811=	synonymous_variant	42/48	ENST00000432829.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DOCK8	ENST00000432829.7	c.5433G>A	p.Glu1811=	synonymous_variant	42/48	1	NM_203447.4

Frequencies

GnomAD3 genomes AF: 0.763 AC: 116031 AN: 151978 Hom.: 45172 Cov.: 31

Gnomad AFR AF: 0.593

Gnomad AMI AF: 0.740

Gnomad AMR AF: 0.848

Gnomad ASJ AF: 0.784

Gnomad EAS AF: 0.994

Gnomad SAS AF: 0.822

Gnomad FIN AF: 0.819

Gnomad MID AF: 0.851

Gnomad NFE AF: 0.816

Gnomad OTH AF: 0.771

GnomAD3 exomes AF: 0.825 AC: 207418 AN: 251418 Hom.: 86529 AF XY: 0.826 AC XY: 112181 AN XY: 135884

Gnomad AFR exome AF: 0.591

Gnomad AMR exome AF: 0.882

Gnomad ASJ exome AF: 0.763

Gnomad EAS exome AF: 0.996

Gnomad SAS exome AF: 0.817

Gnomad FIN exome AF: 0.831

Gnomad NFE exome AF: 0.820

Gnomad OTH exome AF: 0.824

GnomAD4 exome AF: 0.818 AC: 1196128 AN: 1461720 Hom.: 491221 Cov.: 55 AF XY: 0.819 AC XY: 595315 AN XY: 727162

Gnomad4 AFR exome AF: 0.588

Gnomad4 AMR exome AF: 0.878

Gnomad4 ASJ exome AF: 0.765

Gnomad4 EAS exome AF: 0.998

Gnomad4 SAS exome AF: 0.818

Gnomad4 FIN exome AF: 0.830

Gnomad4 NFE exome AF: 0.818

Gnomad4 OTH exome AF: 0.812

GnomAD4 genome AF: 0.763 AC: 116118 AN: 152096 Hom.: 45203 Cov.: 31 AF XY: 0.768 AC XY: 57059 AN XY: 74342

Gnomad4 AFR AF: 0.594

Gnomad4 AMR AF: 0.848

Gnomad4 ASJ AF: 0.784

Gnomad4 EAS AF: 0.994

Gnomad4 SAS AF: 0.822

Gnomad4 FIN AF: 0.819

Gnomad4 NFE AF: 0.816

Gnomad4 OTH AF: 0.773

Alfa AF: 0.794 Hom.: 30437

Bravo AF: 0.758

Asia WGS AF: 0.899 AC: 3127 AN: 3478

EpiCase AF: 0.814

EpiControl AF: 0.820

ClinVar

Significance: Benign

Submissions summary: Benign:10 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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 100% of patients studied by a panel of primary immunodeficiencies. Number of patients: 96. Only high quality variants are reported. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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	Glu1811Glu in exon 42 of DOCK8: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue and is not located wi thin the splice consensus sequence. It has been identified in 39.9% (1756/4406) of African American chromosomes from a broad population by the NHLBI Exome Seque ncing Project (http://evs.gs.washington.edu/EVS; dbSNP rs1887957). -

Combined immunodeficiency due to DOCK8 deficiency Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -
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	Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust	Aug 25, 2015	- -

not provided Benign:1 Other:1

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. -

Autosomal recessive hyper-IgE syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
Cadd	Benign	6.8
Dann	Benign	0.53

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: rs1887957; hg19: chr9-441952; COSMIC: COSV66622581;