rs112321280

Positions:

• chr9-336714-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3 PP5_Moderate

The NM_203447.4(DOCK8):​c.1418A>G​(p.Lys473Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K473N) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DOCK8 NM_203447.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 7.26

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 Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 9-336714-A-G is Pathogenic according to our data. Variant chr9-336714-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 949.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DOCK8	NM_203447.4	c.1418A>G	p.Lys473Arg	missense_variant	12/48	ENST00000432829.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DOCK8	ENST00000432829.7	c.1418A>G	p.Lys473Arg	missense_variant	12/48	1	NM_203447.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Combined immunodeficiency due to DOCK8 deficiency Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 19, 2009

- -

Autosomal recessive hyper-IgE syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Dec 19, 2021

This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 473 of the DOCK8 protein (p.Lys473Arg). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 949). This missense change has been observed in individual(s) with DOCK8 deficiency (PMID: 20004785; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Benign	0.27	T;.;.
Eigen	Uncertain	0.20
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.97	D;D;D
M_CAP	Benign	0.019	T
MetaRNN	Uncertain	0.55	D;D;D
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.4	L;.;.
MutationTaster	Benign	1.0	A;A;A
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-2.4	.;.;N
REVEL	Benign	0.26
Sift	Benign	0.17	.;.;T
Sift4G	Benign	0.090	T;T;T
Polyphen		0.73	P;.;.
Vest4		0.88
MutPred		0.29		Loss of ubiquitination at K473 (P = 0.0022);.;.;
MVP		0.62
MPC		0.28
ClinPred		0.89	D
GERP RS		5.1
Varity_R		0.14
gMVP		0.60

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.54		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.54		Position offset: 0
DS_DL_spliceai		0.54		Position offset: 4

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

Publications

LitVar

Other links and lift over

dbSNP: rs112321280; hg19: chr9-336714;