9-406999-C-T

Position:

chr9-406999-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_203447.4(DOCK8):c.3460C>T(p.Arg1154Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00186 in 1,614,128 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0019 ( 4 hom., cov: 32)

Exomes 𝑓: 0.0019 ( 12 hom. )

Consequence

DOCK8
NM_203447.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:7

Conservation

PhyloP100: 4.71

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 (HGNC:):

DOCK8 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.011115372).

BP6

Variant 9-406999-C-T is Benign according to our data. Variant chr9-406999-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 418766.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=1, Benign=2}. Variant chr9-406999-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00188 (287/152258) while in subpopulation SAS AF= 0.00602 (29/4820). AF 95% confidence interval is 0.0043. There are 4 homozygotes in gnomad4. There are 152 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DOCK8	NM_203447.4 linkuse as main transcript	c.3460C>T	p.Arg1154Cys	missense_variant	28/48	ENST00000432829.7	NP_982272.2	Q8NF50-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DOCK8	ENST00000432829.7 linkuse as main transcript	c.3460C>T	p.Arg1154Cys	missense_variant	28/48	1	NM_203447.4	ENSP00000394888.3		Q8NF50-1

Frequencies

GnomAD3 genomes

AF:

0.00189

AC:

287

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00327

Gnomad ASJ

AF:

0.0242

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00580

Gnomad FIN

AF:

0.000848

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00146

Gnomad OTH

AF:

0.00382

GnomAD3 exomes

AF:

0.00286

AC:

719

AN:

251248

Hom.:

AF XY:

0.00325

AC XY:

441

AN XY:

135772

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00171

Gnomad ASJ exome

AF:

0.0249

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.00679

Gnomad FIN exome

AF:

0.000785

Gnomad NFE exome

AF:

0.00146

Gnomad OTH exome

AF:

0.00245

GnomAD4 exome

AF:

0.00186

AC:

2723

AN:

1461870

Hom.:

Cov.:

AF XY:

0.00210

AC XY:

1527

AN XY:

727232

show subpopulations

Gnomad4 AFR exome

AF:

0.000209

Gnomad4 AMR exome

AF:

0.00152

Gnomad4 ASJ exome

AF:

0.0249

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00692

Gnomad4 FIN exome

AF:

0.00109

Gnomad4 NFE exome

AF:

0.00101

Gnomad4 OTH exome

AF:

0.00290

GnomAD4 genome

AF:

0.00188

AC:

287

AN:

152258

Hom.:

Cov.:

AF XY:

0.00204

AC XY:

152

AN XY:

74444

show subpopulations

Gnomad4 AFR

AF:

0.000144

Gnomad4 AMR

AF:

0.00327

Gnomad4 ASJ

AF:

0.0242

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00602

Gnomad4 FIN

AF:

0.000848

Gnomad4 NFE

AF:

0.00146

Gnomad4 OTH

AF:

0.00379

Alfa

AF:

0.00250

Hom.:

Bravo

AF:

0.00176

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.00156

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00221

AC:

ExAC

AF:

0.00259

AC:

314

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00251

EpiControl

AF:

0.00284

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Combined immunodeficiency due to DOCK8 deficiency

Uncertain:1Benign:2

Benign, criteria provided, single submitter	clinical testing	Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	Dec 10, 2020	- -
Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Uncertain significance, criteria provided, single submitter	clinical testing	Diagnostics Services (NGS), CSIR - Centre For Cellular And Molecular Biology	Apr 17, 2020	The c.3460C>T variant is present in publicly available databases like 1000 Genomes, Exome Variant Server (EVS), Exome Aggregation Consortium (ExAC), Genome Aggregation Database (gnomAD) and dbSNP at low frequency (MAF<0.003), including 3 homozygotes in gnomAD. The variant is also present in our in-house exome database at low frequency (MAF~004), in heterozygous state. The variant was reported earlier to ClinVar database (Accession: VCV000418766.3) with conflicting interpretations of pathogenicity (benign/uncertain significance), however clinical condition was not provided. In-silico pathogenicity prediction programs like PolyPhen-3, MutationTaster2, CADD etc. predicted this variant to be likely deleterious. However there are no documented functional studies to prove this. Due to lack of evidence the variant has been classified as un certain significance. The patient harbors another heterozygous missense variant of uncertain significance (c.3002T>C) in DOCK8 gene. -

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2023	DOCK8: BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 28, 2019	- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Nov 04, 2021

- -

DOCK8-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 02, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Autosomal recessive hyper-IgE syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.11

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.62

D;.;.;T

Eigen

Uncertain

0.65

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.95

D;D;D;D

M_CAP

Benign

0.017

MetaRNN

Benign

0.011

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.2

L;.;.;.

PrimateAI

Uncertain

0.62

PROVEAN

Pathogenic

-6.8

.;.;D;D

REVEL

Benign

0.29

Sift

Pathogenic

0.0

.;.;D;D

Sift4G

Pathogenic

0.0

D;D;D;D

Polyphen

1.0

D;.;.;D

Vest4

0.83

MVP

0.48

MPC

0.31

ClinPred

0.10

GERP RS

5.6

Varity_R

0.75

gMVP

0.54

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