NM_203447.4:c.4785+6C>G

Variant names:

• chr9-432330-C-G
• rs7036567
• NM_203447.4:c.4785+6C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_203447.4(DOCK8):​c.4785+6C>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 0.757 in 1,613,316 control chromosomes in the GnomAD database, including 466,623 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 (38123 hom., cov: 30)
  • Exomes 𝑓: 0.76 (428500 hom.)
• Consequence: DOCK8 NM_203447.4 splice_region, intron
• Scores: Splicing: ADA: 0.00009776
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10 O:1
• Conservation: PhyloP100: 0.213
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 9-432330-C-G is Benign according to our data. Variant chr9-432330-C-G is described in ClinVar as Benign. ClinVar VariationId is 163176.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.4785+6C>G		splice_region_variant, intron_variant	Intron 37 of 47	ENST00000432829.7	NP_982272.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DOCK8	ENST00000432829.7	c.4785+6C>G		splice_region_variant, intron_variant	Intron 37 of 47	1	NM_203447.4	ENSP00000394888.3

Frequencies

GnomAD3 genomes AF: 0.696 AC: 105596 AN: 151788 Hom.: 38106 Cov.: 30

Gnomad AFR AF: 0.487

Gnomad AMI AF: 0.638

Gnomad AMR AF: 0.793

Gnomad ASJ AF: 0.732

Gnomad EAS AF: 0.981

Gnomad SAS AF: 0.689

Gnomad FIN AF: 0.788

Gnomad MID AF: 0.759

Gnomad NFE AF: 0.763

Gnomad OTH AF: 0.711

GnomAD2 exomes AF: 0.766 AC: 192546 AN: 251346 AF XY: 0.763

Gnomad AFR exome AF: 0.481

Gnomad AMR exome AF: 0.852

Gnomad ASJ exome AF: 0.712

Gnomad EAS exome AF: 0.985

Gnomad FIN exome AF: 0.795

Gnomad NFE exome AF: 0.766

Gnomad OTH exome AF: 0.757

GnomAD4 exome AF: 0.763 AC: 1114842 AN: 1461410 Hom.: 428500 Cov.: 47 AF XY: 0.761 AC XY: 553218 AN XY: 727042

African (AFR) AF: 0.476 AC: 15910 AN: 33454

American (AMR) AF: 0.845 AC: 37799 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.713 AC: 18623 AN: 26124

East Asian (EAS) AF: 0.980 AC: 38920 AN: 39696

South Asian (SAS) AF: 0.689 AC: 59416 AN: 86244

European-Finnish (FIN) AF: 0.794 AC: 42390 AN: 53412

Middle Eastern (MID) AF: 0.701 AC: 4039 AN: 5764

European-Non Finnish (NFE) AF: 0.766 AC: 852028 AN: 1111626

Other (OTH) AF: 0.757 AC: 45717 AN: 60378

GnomAD4 genome AF: 0.696 AC: 105662 AN: 151906 Hom.: 38123 Cov.: 30 AF XY: 0.700 AC XY: 51954 AN XY: 74238

African (AFR) AF: 0.487 AC: 20150 AN: 41360

American (AMR) AF: 0.793 AC: 12106 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.732 AC: 2542 AN: 3472

East Asian (EAS) AF: 0.981 AC: 5068 AN: 5166

South Asian (SAS) AF: 0.690 AC: 3320 AN: 4812

European-Finnish (FIN) AF: 0.788 AC: 8309 AN: 10548

Middle Eastern (MID) AF: 0.759 AC: 223 AN: 294

European-Non Finnish (NFE) AF: 0.763 AC: 51864 AN: 67974

Other (OTH) AF: 0.713 AC: 1502 AN: 2106

Alfa AF: 0.730 Hom.: 10715

Bravo AF: 0.690

Asia WGS AF: 0.823 AC: 2862 AN: 3478

EpiCase AF: 0.751

EpiControl AF: 0.763

ClinVar

Significance: Benign

Submissions summary: Benign:10 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

4785+6C>G in intron 37 of DOCK8: This variant is not expected to have clinical s ignificance because it has been identified in 49.3% (2171/4406) of African Ameri can chromosomes from a broad population by the NHLBI Exome Sequencing Project (h ttp://evs.gs.washington.edu/EVS; dbSNP rs7036567). -

-

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 96% of patients studied by a panel of primary immunodeficiencies. Number of patients: 92. Only high quality variants are reported. -

-

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

- -

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

- -

Combined immunodeficiency due to DOCK8 deficiency Benign:2

Jan 13, 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	-0.78
CADD	Benign	6.6
DANN	Benign	0.49
PhyloP100		0.21
Mutation Taster		=88/12	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000098
dbscSNV1_RF	Benign	0.042
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: rs7036567; hg19: chr9-432330;