Genetic Variant DOCK8:c.895-16T>C (chr9-328006-T-C) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_203447.4(DOCK8):c.895-16T>C variant causes a 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 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 2.38

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 rank	MANE	Protein	UniProt
DOCK8	NM_203447.4 link	c.895-16T>C		intron_variant	Intron 8 of 47	ENST00000432829.7	NP_982272.2	Q8NF50-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DOCK8	ENST00000432829.7 link	c.895-16T>C		intron_variant	Intron 8 of 47	1	NM_203447.4	ENSP00000394888.3		Q8NF50-1

Frequencies

GnomAD3 genomes

AF:

0.671

AC:

102042

AN:

151980

Hom.:

34403

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.688

AC XY:

499504

AN XY:

725798

show subpopulations

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.:

AF XY:

0.671

AC XY:

49921

AN XY:

74364

show subpopulations

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

LINK: link

Submissions by phenotype

not specified

Benign:5

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

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 90% of patients studied by a panel of primary immunodeficiencies. Number of patients: 86. Only high quality variants are reported. -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 25, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 -

not provided

Benign:2

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:1

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

-0.71

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over