9-446401-A-G

Position:

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_203447.4(DOCK8):ā€‹c.5612A>Gā€‹(p.Tyr1871Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000471 in 1,614,052 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…ā˜…).

Frequency

Genomes: š‘“ 0.00045 ( 0 hom., cov: 33)
Exomes š‘“: 0.00047 ( 0 hom. )

Consequence

DOCK8
NM_203447.4 missense

Scores

5
5
9

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: 3.45
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 Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.24071813).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
DOCK8NM_203447.4 linkuse as main transcriptc.5612A>G p.Tyr1871Cys missense_variant 44/48 ENST00000432829.7 NP_982272.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
DOCK8ENST00000432829.7 linkuse as main transcriptc.5612A>G p.Tyr1871Cys missense_variant 44/481 NM_203447.4 ENSP00000394888 Q8NF50-1

Frequencies

GnomAD3 genomes
AF:
0.000453
AC:
69
AN:
152170
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000965
Gnomad AMI
AF:
0.0110
Gnomad AMR
AF:
0.0000654
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.0000943
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000764
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.000410
AC:
103
AN:
251454
Hom.:
0
AF XY:
0.000412
AC XY:
56
AN XY:
135906
show subpopulations
Gnomad AFR exome
AF:
0.000123
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.0000992
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.000462
Gnomad NFE exome
AF:
0.000783
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000473
AC:
691
AN:
1461882
Hom.:
0
Cov.:
32
AF XY:
0.000458
AC XY:
333
AN XY:
727242
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.0000447
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.000412
Gnomad4 NFE exome
AF:
0.000588
Gnomad4 OTH exome
AF:
0.000166
GnomAD4 genome
AF:
0.000453
AC:
69
AN:
152170
Hom.:
0
Cov.:
33
AF XY:
0.000363
AC XY:
27
AN XY:
74332
show subpopulations
Gnomad4 AFR
AF:
0.0000965
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.0000943
Gnomad4 NFE
AF:
0.000764
Gnomad4 OTH
AF:
0.000478
Alfa
AF:
0.000541
Hom.:
0
Bravo
AF:
0.000408
TwinsUK
AF:
0.00135
AC:
5
ALSPAC
AF:
0.000519
AC:
2
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.000581
AC:
5
ExAC
AF:
0.000461
AC:
56
EpiCase
AF:
0.000491
EpiControl
AF:
0.000533

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Uncertain:3
Uncertain significance, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
Uncertain significance, no assertion criteria providedclinical testingDiagnostic Laboratory, Department of Genetics, University Medical Center Groningen-- -
Uncertain significance, criteria provided, single submitterclinical testingGeneDxFeb 19, 2016A variant of uncertain significance has been identified in the DOCK8 gene. The Y1803C variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The NHLBI Exome Sequencing Project reports Y1803C was observed in 5/8600 (0.06%) alleles from individuals of European background, indicating it may be a rare variant in this population. The 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 within the DHR-2 domain that is conserved in mammals; however, in silico analysis is inconsistent in its predictions as to whether or not the variant is 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. -
Combined immunodeficiency due to DOCK8 deficiency Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Autosomal recessive hyper-IgE syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 29, 2024This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 1871 of the DOCK8 protein (p.Tyr1871Cys). This variant is present in population databases (rs140403518, gnomAD 0.08%). This variant has not been reported in the literature in individuals affected with DOCK8-related conditions. ClinVar contains an entry for this variant (Variation ID: 418165). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt DOCK8 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.18
BayesDel_addAF
Benign
-0.19
T
BayesDel_noAF
Benign
-0.090
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Benign
0.33
T;.;.;T
Eigen
Uncertain
0.58
Eigen_PC
Uncertain
0.49
FATHMM_MKL
Benign
0.69
D
LIST_S2
Pathogenic
0.98
D;D;D;D
M_CAP
Benign
0.024
T
MetaRNN
Benign
0.24
T;T;T;T
MetaSVM
Benign
-0.85
T
MutationAssessor
Pathogenic
3.4
M;.;.;.
MutationTaster
Benign
1.0
D;D;D;D
PrimateAI
Pathogenic
0.80
T
PROVEAN
Pathogenic
-7.6
.;.;D;D
REVEL
Uncertain
0.34
Sift
Uncertain
0.0010
.;.;D;D
Sift4G
Pathogenic
0.0010
D;D;D;D
Polyphen
1.0
D;.;.;D
Vest4
0.88
MVP
0.41
MPC
0.32
ClinPred
0.70
D
GERP RS
4.0
Varity_R
0.72
gMVP
0.74

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.

Other links and lift over

dbSNP: rs140403518; hg19: chr9-446401; API