chr9-432330-C-G

Position:

• chr9-432330-C-G

Variant summary

Our verdict is Benign. Variant got -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 donor 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. 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_donor_region, intron
• Scores: Splicing: ADA: 0.00009776
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10 O:1
• Conservation: PhyloP100: 0.213

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 -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 id is 163176.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-432330-C-G is described in Lovd as [Benign].
• 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/exons	MANE	Protein	UniProt
DOCK8	NM_203447.4	c.4785+6C>G		splice_donor_region_variant, intron_variant		ENST00000432829.7	NP_982272.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DOCK8	ENST00000432829.7	c.4785+6C>G		splice_donor_region_variant, intron_variant		1	NM_203447.4	ENSP00000394888

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

GnomAD3 exomes AF: 0.766 AC: 192546 AN: 251346 Hom.: 75318 AF XY: 0.763 AC XY: 103642 AN XY: 135856

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 SAS exome AF: 0.688

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

Gnomad4 AFR exome AF: 0.476

Gnomad4 AMR exome AF: 0.845

Gnomad4 ASJ exome AF: 0.713

Gnomad4 EAS exome AF: 0.980

Gnomad4 SAS exome AF: 0.689

Gnomad4 FIN exome AF: 0.794

Gnomad4 NFE exome AF: 0.766

Gnomad4 OTH exome AF: 0.757

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

Gnomad4 AFR AF: 0.487

Gnomad4 AMR AF: 0.793

Gnomad4 ASJ AF: 0.732

Gnomad4 EAS AF: 0.981

Gnomad4 SAS AF: 0.690

Gnomad4 FIN AF: 0.788

Gnomad4 NFE AF: 0.763

Gnomad4 OTH AF: 0.713

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

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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	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). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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 96% of patients studied by a panel of primary immunodeficiencies. Number of patients: 92. Only high quality variants are reported. -

not provided Benign:2 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. -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Combined immunodeficiency due to DOCK8 deficiency Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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	Genome-Nilou Lab	Jul 14, 2021	- -

Autosomal recessive hyper-IgE syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	6.6
DANN	Benign	0.49

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

Publications

LitVar

Other links and lift over

dbSNP: rs7036567; hg19: chr9-432330;