9-433978-A-G

Variant names:

• chr9-433978-A-G
• rs2360712
• NM_203447.4:c.4886+3A>G

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_203447.4(DOCK8):​c.4886+3A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.756 in 1,607,664 control chromosomes in the GnomAD database, including 463,525 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.70 (38454 hom., cov: 32)
  • Exomes 𝑓: 0.76 (425071 hom.)
• Consequence: DOCK8 NM_203447.4 splice_region, intron
• Scores: Splicing: ADA: 0.004113
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10 O:1
• Conservation: PhyloP100: 2.00
• Publications: 13 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.36).
• BP6: Variant 9-433978-A-G is Benign according to our data. Variant chr9-433978-A-G is described in ClinVar as Benign. ClinVar VariationId is 163177.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.958 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DOCK8	NM_203447.4	c.4886+3A>G		splice_region_variant, intron_variant	Intron 38 of 47	ENST00000432829.7	NP_982272.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DOCK8	ENST00000432829.7	c.4886+3A>G		splice_region_variant, intron_variant	Intron 38 of 47	1	NM_203447.4	ENSP00000394888.3

Frequencies

GnomAD3 genomes AF: 0.701 AC: 106442 AN: 151928 Hom.: 38438 Cov.: 32

Gnomad AFR AF: 0.508

Gnomad AMI AF: 0.638

Gnomad AMR AF: 0.795

Gnomad ASJ AF: 0.730

Gnomad EAS AF: 0.981

Gnomad SAS AF: 0.687

Gnomad FIN AF: 0.788

Gnomad MID AF: 0.763

Gnomad NFE AF: 0.761

Gnomad OTH AF: 0.716

GnomAD2 exomes AF: 0.767 AC: 192569 AN: 251210 AF XY: 0.763

Gnomad AFR exome AF: 0.503

Gnomad AMR exome AF: 0.852

Gnomad ASJ exome AF: 0.709

Gnomad EAS exome AF: 0.985

Gnomad FIN exome AF: 0.796

Gnomad NFE exome AF: 0.765

Gnomad OTH exome AF: 0.757

GnomAD4 exome AF: 0.761 AC: 1108163 AN: 1455618 Hom.: 425071 Cov.: 31 AF XY: 0.759 AC XY: 550337 AN XY: 724626

African (AFR) AF: 0.498 AC: 16608 AN: 33364

American (AMR) AF: 0.846 AC: 37837 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.710 AC: 18533 AN: 26100

East Asian (EAS) AF: 0.981 AC: 38927 AN: 39688

South Asian (SAS) AF: 0.688 AC: 59205 AN: 86108

European-Finnish (FIN) AF: 0.795 AC: 42417 AN: 53376

Middle Eastern (MID) AF: 0.708 AC: 4081 AN: 5762

European-Non Finnish (NFE) AF: 0.764 AC: 845089 AN: 1106298

Other (OTH) AF: 0.755 AC: 45466 AN: 60204

GnomAD4 genome AF: 0.700 AC: 106507 AN: 152046 Hom.: 38454 Cov.: 32 AF XY: 0.705 AC XY: 52415 AN XY: 74326

African (AFR) AF: 0.508 AC: 21052 AN: 41418

American (AMR) AF: 0.795 AC: 12164 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.730 AC: 2536 AN: 3472

East Asian (EAS) AF: 0.981 AC: 5083 AN: 5182

South Asian (SAS) AF: 0.688 AC: 3316 AN: 4818

European-Finnish (FIN) AF: 0.788 AC: 8340 AN: 10582

Middle Eastern (MID) AF: 0.762 AC: 224 AN: 294

European-Non Finnish (NFE) AF: 0.761 AC: 51698 AN: 67966

Other (OTH) AF: 0.719 AC: 1515 AN: 2108

Alfa AF: 0.739 Hom.: 40346

Bravo AF: 0.695

Asia WGS AF: 0.821 AC: 2854 AN: 3478

EpiCase AF: 0.749

EpiControl AF: 0.761

ClinVar

Significance: Benign

Submissions summary: Benign:10 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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 97% of patients studied by a panel of primary immunodeficiencies. Number of patients: 93. Only high quality variants are reported. -

Feb 21, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

4886+3A>G in intron 38 of DOCK8: This variant is not expected to have clinical s ignificance because it has been identified in 48.5% (2135/4406) of African Ameri can chromosomes from a broad population by the NHLBI Exome Sequencing Project (h ttp://evs.gs.washington.edu/EVS; dbSNP rs2360712). -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

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. -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Combined immunodeficiency due to DOCK8 deficiency Benign:2

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

- -

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	-0.36
CADD	Benign	18
DANN	Benign	0.90
PhyloP100		2.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0041
dbscSNV1_RF	Benign	0.20
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: rs2360712; hg19: chr9-433978;