chr9-420579-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP3BP4_StrongBP6BS1BS2

The NM_203447.4(DOCK8):ā€‹c.4019A>Gā€‹(p.Tyr1340Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00357 in 1,614,156 control chromosomes in the GnomAD database, including 21 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: š‘“ 0.0027 ( 2 hom., cov: 33)
Exomes š‘“: 0.0037 ( 19 hom. )

Consequence

DOCK8
NM_203447.4 missense

Scores

11
3
5

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:6

Conservation

PhyloP100: 9.22
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

PP3
Multiple lines of computational evidence support a deleterious effect 8: AlphaMissense, Cadd, Eigen, FATHMM_MKL, phyloP100way_vertebrate, PrimateAI, PROVEAN, REVEL [when BayesDel_addAF, max_spliceai, M_CAP, MetaRNN, MutationTaster was below the threshold]
BP4
Computational evidence support a benign effect (MetaRNN=0.026553571).
BP6
Variant 9-420579-A-G is Benign according to our data. Variant chr9-420579-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 372357.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=4, Benign=2, Likely_benign=3}.
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00274 (417/152298) while in subpopulation NFE AF= 0.00365 (248/68030). AF 95% confidence interval is 0.00327. There are 2 homozygotes in gnomad4. There are 216 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
DOCK8NM_203447.4 linkc.4019A>G p.Tyr1340Cys missense_variant Exon 31 of 48 ENST00000432829.7 NP_982272.2 Q8NF50-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
DOCK8ENST00000432829.7 linkc.4019A>G p.Tyr1340Cys missense_variant Exon 31 of 48 1 NM_203447.4 ENSP00000394888.3 Q8NF50-1

Frequencies

GnomAD3 genomes
AF:
0.00274
AC:
417
AN:
152180
Hom.:
2
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000821
Gnomad AMI
AF:
0.00219
Gnomad AMR
AF:
0.00249
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00186
Gnomad FIN
AF:
0.00744
Gnomad MID
AF:
0.00316
Gnomad NFE
AF:
0.00365
Gnomad OTH
AF:
0.00287
GnomAD3 exomes
AF:
0.00271
AC:
681
AN:
251468
Hom.:
2
AF XY:
0.00283
AC XY:
385
AN XY:
135904
show subpopulations
Gnomad AFR exome
AF:
0.000308
Gnomad AMR exome
AF:
0.00173
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00255
Gnomad FIN exome
AF:
0.00684
Gnomad NFE exome
AF:
0.00327
Gnomad OTH exome
AF:
0.00293
GnomAD4 exome
AF:
0.00366
AC:
5351
AN:
1461858
Hom.:
19
Cov.:
31
AF XY:
0.00356
AC XY:
2592
AN XY:
727234
show subpopulations
Gnomad4 AFR exome
AF:
0.000329
Gnomad4 AMR exome
AF:
0.00197
Gnomad4 ASJ exome
AF:
0.0000383
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00220
Gnomad4 FIN exome
AF:
0.00594
Gnomad4 NFE exome
AF:
0.00409
Gnomad4 OTH exome
AF:
0.00323
GnomAD4 genome
AF:
0.00274
AC:
417
AN:
152298
Hom.:
2
Cov.:
33
AF XY:
0.00290
AC XY:
216
AN XY:
74472
show subpopulations
Gnomad4 AFR
AF:
0.000818
Gnomad4 AMR
AF:
0.00248
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00187
Gnomad4 FIN
AF:
0.00744
Gnomad4 NFE
AF:
0.00365
Gnomad4 OTH
AF:
0.00284
Alfa
AF:
0.00305
Hom.:
2
Bravo
AF:
0.00235
TwinsUK
AF:
0.00539
AC:
20
ALSPAC
AF:
0.00649
AC:
25
ESP6500AA
AF:
0.000681
AC:
3
ESP6500EA
AF:
0.00360
AC:
31
ExAC
AF:
0.00253
AC:
307
Asia WGS
AF:
0.000577
AC:
2
AN:
3478
EpiCase
AF:
0.00311
EpiControl
AF:
0.00373

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:4Benign:6
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not specified Uncertain:2Benign:2
May 20, 2016
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

p.Tyr1340Cys in exon 31 of DOCK8: This variant is not expected to have clinical significance because it has been identified in 0.7% (48/6614) of Finnish chromos omes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs116920018). -

Aug 30, 2021
Genetic Services Laboratory, University of Chicago
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

DNA sequence analysis of the DOCK8 gene demonstrated a sequence change, c.4019A>G, in exon 31 that results in an amino acid change, p.Tyr1340Cys. This sequence change has been described in the gnomAD database with a frequency of 0.65% in the non-Finnish European subpopulation and includes 2 homozygous individuals (dbSNP rs116920018). The p.Tyr1340Cys change affects a highly conserved amino acid residue located in a domain of the DOCK8 protein that is not known to be functional. The p.Tyr1340Cys substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This sequence change does not appear to have been previously described in individuals with DOCK8-related disorders. Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Tyr1340Cys change remains unknown at this time. -

Dec 08, 2016
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

A variant of uncertain significance has been identified in the DOCK8 gene. The Y1272C variant has not been published as a germline pathogenic variant, nor has it been reported as a benign variant to our knowledge. The NHLBI Exome Sequencing Project and the 1000 Genomes Project Consortium report Y1272C was observed in 31/8600 (0.36%) alleles and 3/694 (0.43%) from individuals of European and mixed American ancestry, respectively, indicating it may be a rare variant in these populations. Additionally, the variant has been observed in the homozygous state in two unaffected individuals at GeneDx. However, the Y1272C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -

Dec 15, 2023
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant summary: DOCK8 c.4019A>G (p.Tyr1340Cys) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0036 in 1614156 control chromosomes in the gnomAD database, including 21 homozygotes, strongly suggesting the variant is a benign polymorphism. c.4019A>G has been reported in the literature in the heterozygous state in an individual with some clinical features of Combined Immunodeficiency Due To DOCK8 Deficiency, without strong evidence for causality (Similuk_2022). This report does not provide unequivocal conclusions about association of the variant with Combined Immunodeficiency Due To DOCK8 Deficiency. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 35753512). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Four submitters classified the variant as benign/likely benign and four classified it as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign. -

Combined immunodeficiency due to DOCK8 deficiency Uncertain:1Benign:1
Apr 27, 2017
Illumina Laboratory Services, Illumina
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Mar 30, 2021
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

DOCK8 NM_203447.3 exon 31 p.Tyr1340Cys (c.4019A>G):This variant has not been reported in the literature but is present in 0.6% (175/25788) of European (Finnish) alleles, including 1 homozygote in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs116920018). This variant is present in ClinVar (Variation ID:372357). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. Splice prediction tools suggest that this variant may affect splicing. However, further studies are needed to understand its impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

not provided Uncertain:1Benign:1
Sep 30, 2022
Mayo Clinic Laboratories, Mayo Clinic
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Oct 01, 2023
CeGaT Center for Human Genetics Tuebingen
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

DOCK8: BS2 -

DOCK8-related disorder Benign:1
May 22, 2020
PreventionGenetics, part of Exact Sciences
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

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). -

Benign:1
Jan 30, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.72
BayesDel_addAF
Benign
-0.073
T
BayesDel_noAF
Uncertain
0.13
CADD
Pathogenic
27
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.82
D;.;.;T
Eigen
Pathogenic
0.98
Eigen_PC
Pathogenic
0.93
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Pathogenic
1.0
D;D;D;D
M_CAP
Benign
0.044
D
MetaRNN
Benign
0.027
T;T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Uncertain
2.8
M;.;.;.
PrimateAI
Pathogenic
0.86
D
PROVEAN
Pathogenic
-8.4
.;.;D;D
REVEL
Pathogenic
0.65
Sift
Pathogenic
0.0
.;.;D;D
Sift4G
Pathogenic
0.0
D;D;D;D
Polyphen
1.0
D;.;.;D
Vest4
0.95
MVP
0.62
MPC
0.33
ClinPred
0.088
T
GERP RS
6.0
Varity_R
0.78
gMVP
0.82

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.

Other links and lift over

dbSNP: rs116920018; hg19: chr9-420579; COSMIC: COSV101210081; API