rs1887957

Variant names:

• chr9-441952-G-A
• rs1887957
• NM_203447.4:c.5433G>A

Your query was ambiguous. Multiple possible variants found:

• chr9-441952-G-A
• chr9-441952-G-C
• chr9-441952-G-T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_203447.4(DOCK8):​c.5433G>A​(p.Glu1811Glu) 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:11 O:1
• Conservation: PhyloP100: 0.269
• Publications: 26 publications found

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 Gene-Disease associations (from GenCC):

• combined immunodeficiency due to DOCK8 deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: Orphanet, ClinGen, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, Genomics England PanelApp
• autosomal dominant non-syndromic intellectual disability

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• complex neurodevelopmental disorder

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 178771.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
DOCK8	NM_203447.4	c.5433G>A	p.Glu1811Glu	synonymous_variant	Exon 42 of 48	ENST00000432829.7	NP_982272.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DOCK8	ENST00000432829.7	c.5433G>A	p.Glu1811Glu	synonymous_variant	Exon 42 of 48	1	NM_203447.4	ENSP00000394888.3

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

GnomAD2 exomes AF: 0.825 AC: 207418 AN: 251418 AF XY: 0.826

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 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

African (AFR) AF: 0.588 AC: 19665 AN: 33472

American (AMR) AF: 0.878 AC: 39290 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.765 AC: 19996 AN: 26128

East Asian (EAS) AF: 0.998 AC: 39587 AN: 39686

South Asian (SAS) AF: 0.818 AC: 70518 AN: 86250

European-Finnish (FIN) AF: 0.830 AC: 44330 AN: 53398

Middle Eastern (MID) AF: 0.785 AC: 4523 AN: 5764

European-Non Finnish (NFE) AF: 0.818 AC: 909191 AN: 1111908

Other (OTH) AF: 0.812 AC: 49028 AN: 60390

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

African (AFR) AF: 0.594 AC: 24619 AN: 41466

American (AMR) AF: 0.848 AC: 12963 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.784 AC: 2722 AN: 3472

East Asian (EAS) AF: 0.994 AC: 5142 AN: 5172

South Asian (SAS) AF: 0.822 AC: 3966 AN: 4824

European-Finnish (FIN) AF: 0.819 AC: 8656 AN: 10574

Middle Eastern (MID) AF: 0.850 AC: 250 AN: 294

European-Non Finnish (NFE) AF: 0.816 AC: 55498 AN: 67990

Other (OTH) AF: 0.773 AC: 1627 AN: 2106

Alfa AF: 0.792 Hom.: 31958

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:11 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Feb 21, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). -

Nov 12, 2023

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Combined immunodeficiency due to DOCK8 deficiency Benign:3

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 25, 2015

Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2 Other:1

-

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

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. -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	6.8
DANN	Benign	0.53
PhyloP100		0.27
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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