chr9-418193-G-T

Position:

chr9-418193-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The ENST00000432829.7(DOCK8):c.3826G>T(p.Val1276Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000204 in 1,614,202 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1276M) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0011 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00011 ( 2 hom. )

Consequence

DOCK8
ENST00000432829.7 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.455

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 (MetaRNN=0.004193485).

BP6

Variant 9-418193-G-T is Benign according to our data. Variant chr9-418193-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 178768.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-418193-G-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00109 (166/152332) while in subpopulation AFR AF= 0.00346 (144/41582). AF 95% confidence interval is 0.003. There are 0 homozygotes in gnomad4. There are 71 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DOCK8	NM_203447.4 linkuse as main transcript	c.3826G>T	p.Val1276Leu	missense_variant	30/48	ENST00000432829.7	NP_982272.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DOCK8	ENST00000432829.7 linkuse as main transcript	c.3826G>T	p.Val1276Leu	missense_variant	30/48	1	NM_203447.4	ENSP00000394888		Q8NF50-1

Frequencies

GnomAD3 genomes

AF:

0.00108

AC:

165

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00345

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00118

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.000318

AC:

AN:

251474

Hom.:

AF XY:

0.000250

AC XY:

AN XY:

135912

show subpopulations

Gnomad AFR exome

AF:

0.00437

Gnomad AMR exome

AF:

0.000173

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000112

AC:

163

AN:

1461870

Hom.:

Cov.:

AF XY:

0.000102

AC XY:

AN XY:

727232

show subpopulations

Gnomad4 AFR exome

AF:

0.00361

Gnomad4 AMR exome

AF:

0.000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.000331

GnomAD4 genome

AF:

0.00109

AC:

166

AN:

152332

Hom.:

Cov.:

AF XY:

0.000953

AC XY:

AN XY:

74496

show subpopulations

Gnomad4 AFR

AF:

0.00346

Gnomad4 AMR

AF:

0.00118

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000188

Hom.:

Bravo

AF:

0.00153

ESP6500AA

AF:

0.00295

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000313

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Dec 27, 2013

Val1276Leu in exon30 of DOCK8: This variant is not expected to have clinical sig nificance because it has been identified in 0.3% (13/4406) of African American c hromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/E VS; dbSNP rs148796842). In addition, valine at position 1276 is poorly conserved in evolution, suggesting that a change may be tolerated. -

DOCK8-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 12, 2022

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

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 19, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.68

CADD

Benign

2.6

DANN

Benign

0.55

DEOGEN2

Benign

0.091

T;.;.;T

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.027

LIST_S2

Benign

0.58

T;T;T;T

M_CAP

Benign

0.0035

MetaRNN

Benign

0.0042

T;T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

-0.81

N;.;.;.

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Benign

0.29

PROVEAN

Benign

0.030

.;.;N;N

REVEL

Benign

0.030

Sift

Benign

0.52

.;.;T;T

Sift4G

Benign

0.90

T;T;T;T

Polyphen

0.0

B;.;.;B

Vest4

0.11

MutPred

0.53

Loss of sheet (P = 0.0126);.;.;.;

MVP

0.33

MPC

0.042

ClinPred

0.00033

GERP RS

-0.14

Varity_R

0.018

gMVP

0.14

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