chr9-414824-C-T

Position:

chr9-414824-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBS1BS2

The NM_203447.4(DOCK8):c.3573C>T(p.Ser1191=) variant causes a synonymous change. The variant allele was found at a frequency of 0.00937 in 1,614,196 control chromosomes in the GnomAD database, including 107 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0065 ( 6 hom., cov: 33)

Exomes 𝑓: 0.0097 ( 101 hom. )

Consequence

DOCK8
NM_203447.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 3.86

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 -18 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.19).

BP6

Variant 9-414824-C-T is Benign according to our data. Variant chr9-414824-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 163175.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-414824-C-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00652 (993/152314) while in subpopulation NFE AF= 0.0101 (690/68026). AF 95% confidence interval is 0.00952. There are 6 homozygotes in gnomad4. There are 437 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DOCK8	NM_203447.4 linkuse as main transcript	c.3573C>T	p.Ser1191=	synonymous_variant	29/48	ENST00000432829.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DOCK8	ENST00000432829.7 linkuse as main transcript	c.3573C>T	p.Ser1191=	synonymous_variant	29/48	1	NM_203447.4		Q8NF50-1

Frequencies

GnomAD3 genomes

AF:

0.00652

AC:

993

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00224

Gnomad AMI

AF:

0.0592

Gnomad AMR

AF:

0.00746

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00207

Gnomad FIN

AF:

0.000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0101

Gnomad OTH

AF:

0.0105

GnomAD3 exomes

AF:

0.00570

AC:

1434

AN:

251466

Hom.:

AF XY:

0.00553

AC XY:

752

AN XY:

135908

show subpopulations

Gnomad AFR exome

AF:

0.00209

Gnomad AMR exome

AF:

0.00515

Gnomad ASJ exome

AF:

0.000198

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00140

Gnomad FIN exome

AF:

0.00106

Gnomad NFE exome

AF:

0.00981

Gnomad OTH exome

AF:

0.00619

GnomAD4 exome

AF:

0.00967

AC:

14133

AN:

1461882

Hom.:

101

Cov.:

AF XY:

0.00925

AC XY:

6726

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.00206

Gnomad4 AMR exome

AF:

0.00539

Gnomad4 ASJ exome

AF:

0.000230

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00141

Gnomad4 FIN exome

AF:

0.00129

Gnomad4 NFE exome

AF:

0.0117

Gnomad4 OTH exome

AF:

0.0101

GnomAD4 genome

AF:

0.00652

AC:

993

AN:

152314

Hom.:

Cov.:

AF XY:

0.00587

AC XY:

437

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.00224

Gnomad4 AMR

AF:

0.00745

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00207

Gnomad4 FIN

AF:

0.000942

Gnomad4 NFE

AF:

0.0101

Gnomad4 OTH

AF:

0.0104

Alfa

AF:

0.00758

Hom.:

Bravo

AF:

0.00760

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.0104

EpiControl

AF:

0.00984

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	Ser1191Ser in exon 29 of DOCK8: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue and is not located wi thin the splice consensus sequence. It has been identified in 1.1% (92/8600) of European American chromosomes from a broad population by the NHLBI Exome Sequenc ing Project (http://evs.gs.washington.edu/EVS; dbSNP rs13285348). -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 22, 2021	- -

not provided

Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	DOCK8: BP4, BS2 -

Combined immunodeficiency due to DOCK8 deficiency

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

Autosomal recessive hyper-IgE syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.19

CADD

Benign

8.5

DANN

Benign

0.76

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