9-328006-T-C

Position:

• chr9-328006-T-C

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.895-16T>C variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.684 in 1,610,546 control chromosomes in the GnomAD database, including 377,736 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.67 (34415 hom., cov: 33)
  • Exomes 𝑓: 0.69 (343321 hom.)
• Consequence: DOCK8 NM_203447.4 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 2.38

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=-0.71).
• BP6: Variant 9-328006-T-C is Benign according to our data. Variant chr9-328006-T-C is described in ClinVar as [Benign]. Clinvar id is 263271.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-328006-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.747 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DOCK8	NM_203447.4	c.895-16T>C		splice_polypyrimidine_tract_variant, intron_variant		ENST00000432829.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DOCK8	ENST00000432829.7	c.895-16T>C		splice_polypyrimidine_tract_variant, intron_variant		1	NM_203447.4

Frequencies

GnomAD3 genomes AF: 0.671 AC: 102042 AN: 151980 Hom.: 34403 Cov.: 33

Gnomad AFR AF: 0.655

Gnomad AMI AF: 0.789

Gnomad AMR AF: 0.668

Gnomad ASJ AF: 0.570

Gnomad EAS AF: 0.714

Gnomad SAS AF: 0.768

Gnomad FIN AF: 0.660

Gnomad MID AF: 0.566

Gnomad NFE AF: 0.679

Gnomad OTH AF: 0.655

GnomAD3 exomes AF: 0.688 AC: 172761 AN: 251148 Hom.: 59602 AF XY: 0.692 AC XY: 93944 AN XY: 135772

Gnomad AFR exome AF: 0.658

Gnomad AMR exome AF: 0.683

Gnomad ASJ exome AF: 0.575

Gnomad EAS exome AF: 0.726

Gnomad SAS exome AF: 0.769

Gnomad FIN exome AF: 0.670

Gnomad NFE exome AF: 0.680

Gnomad OTH exome AF: 0.672

GnomAD4 exome AF: 0.685 AC: 999366 AN: 1458448 Hom.: 343321 Cov.: 34 AF XY: 0.688 AC XY: 499504 AN XY: 725798

Gnomad4 AFR exome AF: 0.651

Gnomad4 AMR exome AF: 0.680

Gnomad4 ASJ exome AF: 0.573

Gnomad4 EAS exome AF: 0.719

Gnomad4 SAS exome AF: 0.766

Gnomad4 FIN exome AF: 0.671

Gnomad4 NFE exome AF: 0.683

Gnomad4 OTH exome AF: 0.669

GnomAD4 genome AF: 0.671 AC: 102099 AN: 152098 Hom.: 34415 Cov.: 33 AF XY: 0.671 AC XY: 49921 AN XY: 74364

Gnomad4 AFR AF: 0.654

Gnomad4 AMR AF: 0.668

Gnomad4 ASJ AF: 0.570

Gnomad4 EAS AF: 0.714

Gnomad4 SAS AF: 0.768

Gnomad4 FIN AF: 0.660

Gnomad4 NFE AF: 0.679

Gnomad4 OTH AF: 0.660

Alfa AF: 0.659 Hom.: 7645

Bravo AF: 0.669

Asia WGS AF: 0.751 AC: 2611 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

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	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 25, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -
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 90% of patients studied by a panel of primary immunodeficiencies. Number of patients: 86. Only high quality variants are reported. -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Combined immunodeficiency due to DOCK8 deficiency Benign:1

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	-0.71
CADD	Benign	8.1
DANN	Benign	0.83

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: rs2296828; hg19: chr9-328006; COSMIC: COSV66634158;