Genetic Variant DOCK8:c.-152+3390G>C (chr9-214706-G-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 XM_047423927.1(DOCK8):c.-152+3390G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.452 in 1,555,630 control chromosomes in the GnomAD database, including 161,786 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.47 ( 17266 hom., cov: 34)

Exomes 𝑓: 0.45 ( 144520 hom. )

Consequence

DOCK8
XM_047423927.1 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.960

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:

DOCK8-AS1 (HGNC:26436): (DOCK8 antisense RNA 1)

DOCK8-AS1 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 (MetaRNN=1.3728811E-6).

BP6

Variant 9-214706-G-C is Benign according to our data. Variant chr9-214706-G-C is described in ClinVar as [Benign]. Clinvar id is 1224206.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.721 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DOCK8	NM_203447.4 link	c.-271G>C		upstream_gene_variant		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.-271G>C		upstream_gene_variant		1	NM_203447.4	ENSP00000394888.3		Q8NF50-1

Frequencies

GnomAD3 genomes

AF:

0.473

AC:

71816

AN:

151932

Hom.:

17246

Cov.:

show subpopulations

Gnomad AFR

AF:

0.494

Gnomad AMI

AF:

0.476

Gnomad AMR

AF:

0.511

Gnomad ASJ

AF:

0.395

Gnomad EAS

AF:

0.741

Gnomad SAS

AF:

0.524

Gnomad FIN

AF:

0.428

Gnomad MID

AF:

0.490

Gnomad NFE

AF:

0.437

Gnomad OTH

AF:

0.502

GnomAD3 exomes

AF:

0.496

AC:

75949

AN:

153120

Hom.:

19394

AF XY:

0.496

AC XY:

41559

AN XY:

83754

show subpopulations

Gnomad AFR exome

AF:

0.491

Gnomad AMR exome

AF:

0.572

Gnomad ASJ exome

AF:

0.405

Gnomad EAS exome

AF:

0.726

Gnomad SAS exome

AF:

0.522

Gnomad FIN exome

AF:

0.436

Gnomad NFE exome

AF:

0.439

Gnomad OTH exome

AF:

0.490

GnomAD4 exome

AF:

0.450

AC:

631301

AN:

1403586

Hom.:

144520

Cov.:

AF XY:

0.452

AC XY:

313192

AN XY:

693300

show subpopulations

Gnomad4 AFR exome

AF:

0.499

Gnomad4 AMR exome

AF:

0.568

Gnomad4 ASJ exome

AF:

0.407

Gnomad4 EAS exome

AF:

0.722

Gnomad4 SAS exome

AF:

0.526

Gnomad4 FIN exome

AF:

0.442

Gnomad4 NFE exome

AF:

0.430

Gnomad4 OTH exome

AF:

0.469

GnomAD4 genome

AF:

0.473

AC:

71894

AN:

152044

Hom.:

17266

Cov.:

AF XY:

0.478

AC XY:

35494

AN XY:

74316

show subpopulations

Gnomad4 AFR

AF:

0.494

Gnomad4 AMR

AF:

0.511

Gnomad4 ASJ

AF:

0.395

Gnomad4 EAS

AF:

0.741

Gnomad4 SAS

AF:

0.524

Gnomad4 FIN

AF:

0.428

Gnomad4 NFE

AF:

0.437

Gnomad4 OTH

AF:

0.509

Alfa

AF:

0.368

Hom.:

1799

Bravo

AF:

0.487

TwinsUK

AF:

0.413

AC:

1533

ALSPAC

AF:

0.443

AC:

1709

ESP6500AA

AF:

0.425

AC:

1470

ESP6500EA

AF:

0.371

AC:

2548

ExAC

AF:

0.413

AC:

40374

Asia WGS

AF:

0.654

AC:

2269

AN:

3470

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 26, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.78

BayesDel_noAF

Benign

-0.76

CADD

Benign

DANN

Benign

0.65

DEOGEN2

Benign

0.053

Eigen

Benign

-0.84

Eigen_PC

Benign

-0.74

FATHMM_MKL

Benign

0.025

LIST_S2

Benign

0.21

MetaRNN

Benign

0.0000014

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

PROVEAN

Benign

3.3

REVEL

Benign

0.091

Sift4G

Pathogenic

0.0

Polyphen

0.0

Vest4

0.019

MPC

0.17

ClinPred

0.012

GERP RS

1.7

Varity_R

0.17

gMVP

0.0084

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