rs1554662110

Positions:

• chr9-304704-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_203447.4(DOCK8):​c.528G>C​(p.Gln176His) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: DOCK8 NM_203447.4 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.30

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DOCK8	NM_203447.4	c.528G>C	p.Gln176His	missense_variant, splice_region_variant	5/48	ENST00000432829.7	NP_982272.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DOCK8	ENST00000432829.7	c.528G>C	p.Gln176His	missense_variant, splice_region_variant	5/48	1	NM_203447.4	ENSP00000394888

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal recessive hyper-IgE syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 24, 2017

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. Nucleotide substitutions within the consensus splice site are relatively common causes of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with DOCK8-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces glutamine with histidine at codon 176 of the DOCK8 protein (p.Gln176His). The glutamine residue is moderately conserved and there is a small physicochemical difference between glutamine and histidine. This variant also falls at the last nucleotide of exon 5 of the DOCK8 coding sequence, which is part of the consensus splice site for this exon. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.39
CADD	Pathogenic	33
DANN	Uncertain	0.99
DEOGEN2	Benign	0.16	T;.;.
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.78	T;T;T
M_CAP	Benign	0.0045	T
MetaRNN	Benign	0.40	T;T;T
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.1	M;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.6	.;.;N
REVEL	Benign	0.079
Sift	Benign	0.085	.;.;T
Sift4G	Benign	0.11	T;T;T
Polyphen		0.29	B;.;.
Vest4		0.52
MutPred		0.27		Gain of glycosylation at S171 (P = 0.1401);.;.;
MVP		0.41
MPC		0.10
ClinPred		0.60	D
GERP RS		6.0
Varity_R		0.10
gMVP		0.51

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.88		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.88		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1554662110; hg19: chr9-304704;