rs200689054

Positions:

chr9-215028-A-G

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2BP4_StrongBP6BS1

The NM_203447.4(DOCK8):c.52A>G(p.Arg18Gly) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000163 in 1,583,204 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R18K) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00094 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000080 ( 0 hom. )

Consequence

DOCK8
NM_203447.4 missense, splice_region

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 4.38

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 -7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.031262726).

BP6

Variant 9-215028-A-G is Benign according to our data. Variant chr9-215028-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 429234.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00094 (143/152186) while in subpopulation AFR AF= 0.0033 (137/41498). AF 95% confidence interval is 0.00285. There are 0 homozygotes in gnomad4. There are 62 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DOCK8	NM_203447.4 linkuse as main transcript	c.52A>G	p.Arg18Gly	missense_variant, splice_region_variant	1/48	ENST00000432829.7
DOCK8-AS1	NR_160804.1 linkuse as main transcript	n.723T>C		non_coding_transcript_exon_variant	1/1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DOCK8	ENST00000432829.7 linkuse as main transcript	c.52A>G	p.Arg18Gly	missense_variant, splice_region_variant	1/48	1	NM_203447.4		Q8NF50-1
DOCK8-AS1	ENST00000648587.1 linkuse as main transcript	n.714T>C		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes

AF:

0.000940

AC:

143

AN:

152076

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00331

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

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:

0.00

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.000187

AC:

AN:

192762

Hom.:

AF XY:

0.000138

AC XY:

AN XY:

108468

show subpopulations

Gnomad AFR exome

AF:

0.00336

Gnomad AMR exome

AF:

0.000129

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:

0.0000234

Gnomad OTH exome

AF:

0.000205

GnomAD4 exome

AF:

0.0000804

AC:

115

AN:

1431018

Hom.:

Cov.:

112

AF XY:

0.0000675

AC XY:

AN XY:

711260

show subpopulations

Gnomad4 AFR exome

AF:

0.00295

Gnomad4 AMR exome

AF:

0.000117

Gnomad4 ASJ exome

AF:

0.0000393

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000120

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000181

Gnomad4 OTH exome

AF:

0.000236

GnomAD4 genome

AF:

0.000940

AC:

143

AN:

152186

Hom.:

Cov.:

AF XY:

0.000833

AC XY:

AN XY:

74420

show subpopulations

Gnomad4 AFR

AF:

0.00330

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000405

Hom.:

Bravo

AF:

0.00102

ESP6500AA

AF:

0.000894

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000238

AC:

Asia WGS

AF:

0.000290

AC:

AN:

3466

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 07, 2015

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jan 31, 2022

In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge -

Autosomal recessive hyper-IgE syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.92

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.20

CADD

Uncertain

DANN

Benign

0.97

DEOGEN2

Uncertain

0.51

Eigen

Benign

0.12

Eigen_PC

Benign

0.054

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.92

M_CAP

Pathogenic

0.57

MetaRNN

Benign

0.031

MetaSVM

Benign

-1.1

MutationTaster

Benign

0.87

D;D;D

PrimateAI

Uncertain

0.70

Sift4G

Uncertain

0.018

Polyphen

0.019

Vest4

0.69

MVP

0.64

ClinPred

0.039

GERP RS

3.7

Varity_R

0.18

gMVP

0.51

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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