9-428369-C-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BS1_Supporting

The NM_203447.4(DOCK8):c.4346C>T(p.Ser1449Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000102 in 1,614,110 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000085 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00010 (1 hom.)
• Consequence: DOCK8 NM_203447.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:1
• Conservation: PhyloP100: 2.40

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_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13888994).
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000104 (152/1461866) while in subpopulation MID AF= 0.00956 (55/5756). AF 95% confidence interval is 0.00754. There are 1 homozygotes in gnomad4_exome. There are 83 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DOCK8	NM_203447.4	c.4346C>T	p.Ser1449Leu	missense_variant	35/48	ENST00000432829.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DOCK8	ENST00000432829.7	c.4346C>T	p.Ser1449Leu	missense_variant	35/48	1	NM_203447.4

Frequencies

GnomAD3 genomes AF: 0.0000855 AC: 13 AN: 152126 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000756 AC: 19 AN: 251438 Hom.: 0 AF XY: 0.0000662 AC XY: 9 AN XY: 135890

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000173

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000703

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000104 AC: 152 AN: 1461866 Hom.: 1 Cov.: 32 AF XY: 0.000114 AC XY: 83 AN XY: 727238

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.000157

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000209

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000495

Gnomad4 OTH exome AF: 0.000182

GnomAD4 genome AF: 0.0000854 AC: 13 AN: 152244 Hom.: 0 Cov.: 32 AF XY: 0.0000672 AC XY: 5 AN XY: 74432

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000180 Hom.: 0

Bravo AF: 0.000132

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000824 AC: 10

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Combined immunodeficiency due to DOCK8 deficiency Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Oct 05, 2022	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 1449 of the DOCK8 protein (p.Ser1449Leu). This variant is present in population databases (rs370123223, gnomAD 0.02%). This missense change has been observed in individual(s) with DOCK8 deficiency (PMID: 27890707). ClinVar contains an entry for this variant (Variation ID: 386550). 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. 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Jun 03, 2020	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 29, 2022	- -

DOCK8-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 28, 2023

The DOCK8 c.4346C>T variant is predicted to result in the amino acid substitution p.Ser1449Leu. This variant has been reported in the homozygous state in three related Saudi patients from a highly consanguineous family (Al Shekaili et al. 2017. PubMed ID: 27890707). Of note, these individuals were also homozygous for a splicing variant, c.4626+5G>A, in DOCK8 that was predicted to impact splicing based on splicing predication programs and abolish protein product via western blot analysis (Alamut Visual Plus v1.6.1; Al Shekaili et al. 2017. PubMed ID: 27890707). This variant was also reported in the compound heterozygous state in an individual with suspected primary immunodeficiency (Table E2 - Platt et al. 2021. PubMed ID: 32888943). This variant is reported in 0.017% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/9-428369-C-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Apr 09, 2018

This variant is associated with the following publications: (PMID: 27890707, 32888943) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.28
Cadd	Benign	23
Dann	Uncertain	0.98
DEOGEN2	Benign	0.13	T;.;.;T
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.063
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.92	D;D;D;D
M_CAP	Benign	0.0094	T
MetaRNN	Benign	0.14	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N;.;.;.
MutationTaster	Benign	0.95	D;D;D;D
PrimateAI	Uncertain	0.55	T
PROVEAN	Pathogenic	-5.8	D;.;N;N
REVEL	Benign	0.028
Sift	Pathogenic	0.0	D;.;T;T
Sift4G	Benign	0.76	T;T;T;T
Polyphen		0.0050	B;.;.;B
Vest4		0.36
MVP		0.74
MPC		0.040
ClinPred		0.11	T
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.043
gMVP		0.20

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

Other links and lift over

dbSNP: rs370123223; hg19: chr9-428369;