Genetic Variant DOCK8:c.-152+3403C>T (chr9-214719-C-T) – 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+3403C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0359 in 1,538,384 control chromosomes in the GnomAD database, including 1,158 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.028 ( 82 hom., cov: 34)

Exomes 𝑓: 0.037 ( 1076 hom. )

Consequence

DOCK8
XM_047423927.1 intron

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -1.02

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.63).

BP6

Variant 9-214719-C-T is Benign according to our data. Variant chr9-214719-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 1220363.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0543 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DOCK8	NM_203447.4 link	c.-258C>T		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.-258C>T		upstream_gene_variant		1	NM_203447.4	ENSP00000394888.3		Q8NF50-1

Frequencies

GnomAD3 genomes

AF:

0.0277

AC:

4221

AN:

152134

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00704

Gnomad AMI

AF:

0.0121

Gnomad AMR

AF:

0.0340

Gnomad ASJ

AF:

0.0395

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0157

Gnomad FIN

AF:

0.0193

Gnomad MID

AF:

0.0764

Gnomad NFE

AF:

0.0423

Gnomad OTH

AF:

0.0373

GnomAD3 exomes

AF:

0.0317

AC:

4102

AN:

129232

Hom.:

100

AF XY:

0.0319

AC XY:

2262

AN XY:

70856

show subpopulations

Gnomad AFR exome

AF:

0.0101

Gnomad AMR exome

AF:

0.0246

Gnomad ASJ exome

AF:

0.0419

Gnomad EAS exome

AF:

0.000114

Gnomad SAS exome

AF:

0.0163

Gnomad FIN exome

AF:

0.0216

Gnomad NFE exome

AF:

0.0505

Gnomad OTH exome

AF:

0.0430

GnomAD4 exome

AF:

0.0368

AC:

51059

AN:

1386138

Hom.:

1076

Cov.:

AF XY:

0.0364

AC XY:

24868

AN XY:

683604

show subpopulations

Gnomad4 AFR exome

AF:

0.00699

Gnomad4 AMR exome

AF:

0.0233

Gnomad4 ASJ exome

AF:

0.0343

Gnomad4 EAS exome

AF:

0.0000870

Gnomad4 SAS exome

AF:

0.0150

Gnomad4 FIN exome

AF:

0.0225

Gnomad4 NFE exome

AF:

0.0416

Gnomad4 OTH exome

AF:

0.0332

GnomAD4 genome

AF:

0.0277

AC:

4217

AN:

152246

Hom.:

Cov.:

AF XY:

0.0262

AC XY:

1947

AN XY:

74448

show subpopulations

Gnomad4 AFR

AF:

0.00702

Gnomad4 AMR

AF:

0.0339

Gnomad4 ASJ

AF:

0.0395

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0155

Gnomad4 FIN

AF:

0.0193

Gnomad4 NFE

AF:

0.0424

Gnomad4 OTH

AF:

0.0364

Alfa

AF:

0.0338

Hom.:

Bravo

AF:

0.0272

Asia WGS

AF:

0.00897

AC:

AN:

3470

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jul 07, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.63

CADD

Benign

9.2

DANN

Benign

0.95

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