rs139391329

Positions:

• chr9-312088-C-A
• chr9-312088-C-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_203447.4(DOCK8):​c.663C>A​(p.Asp221Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00235 in 1,614,224 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 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 0.0017 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0024 (9 hom.)
• Consequence: DOCK8 NM_203447.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 1.64

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 Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004763007).
• BP6: Variant 9-312088-C-A is Benign according to our data. Variant chr9-312088-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 366546.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1, Benign=1}. Variant chr9-312088-C-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00169 (257/152340) while in subpopulation NFE AF= 0.00281 (191/68032). AF 95% confidence interval is 0.00248. There are 0 homozygotes in gnomad4. There are 123 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DOCK8	NM_203447.4	c.663C>A	p.Asp221Glu	missense_variant	6/48	ENST00000432829.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DOCK8	ENST00000432829.7	c.663C>A	p.Asp221Glu	missense_variant	6/48	1	NM_203447.4

Frequencies

GnomAD3 genomes AF: 0.00169 AC: 257 AN: 152222 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000748

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.00179

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00281

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00175 AC: 440 AN: 251414 Hom.: 1 AF XY: 0.00183 AC XY: 248 AN XY: 135876

Gnomad AFR exome AF: 0.000738

Gnomad AMR exome AF: 0.000463

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00252

Gnomad FIN exome AF: 0.00139

Gnomad NFE exome AF: 0.00255

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.00242 AC: 3542 AN: 1461884 Hom.: 9 Cov.: 31 AF XY: 0.00241 AC XY: 1750 AN XY: 727246

Gnomad4 AFR exome AF: 0.000418

Gnomad4 AMR exome AF: 0.000402

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00279

Gnomad4 FIN exome AF: 0.00129

Gnomad4 NFE exome AF: 0.00279

Gnomad4 OTH exome AF: 0.00139

GnomAD4 genome AF: 0.00169 AC: 257 AN: 152340 Hom.: 0 Cov.: 32 AF XY: 0.00165 AC XY: 123 AN XY: 74488

Gnomad4 AFR AF: 0.000746

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00207

Gnomad4 FIN AF: 0.00179

Gnomad4 NFE AF: 0.00281

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00227 Hom.: 1

Bravo AF: 0.00144

TwinsUK AF: 0.00593 AC: 22

ALSPAC AF: 0.00337 AC: 13

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00291 AC: 25

ExAC AF: 0.00173 AC: 210

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00218

EpiControl AF: 0.00124

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 10, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	DOCK8: BP4, BS2 -

Combined immunodeficiency due to DOCK8 deficiency Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This 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 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 25, 2024

- -

DOCK8-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 31, 2022

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). -

Intellectual disability Benign:1

Likely benign, no assertion criteria provided

clinical testing

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Jan 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	15
DANN	Benign	0.29
DEOGEN2	Benign	0.10	T;.;.
Eigen	Benign	-0.92
Eigen_PC	Benign	-0.68
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.71	T;T;T
M_CAP	Benign	0.0042	T
MetaRNN	Benign	0.0048	T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-0.93	N;.;.
MutationTaster	Benign	0.76	D;N;N
PrimateAI	Benign	0.43	T
REVEL	Benign	0.057
Sift4G	Benign	1.0	T;T;T
Polyphen		0.0	B;.;.
Vest4		0.16
MutPred		0.20		Gain of helix (P = 0.0225);.;.;
MVP		0.20
MPC		0.042
ClinPred		0.0056	T
GERP RS		2.8
Varity_R		0.069
gMVP		0.23

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs139391329; hg19: chr9-312088;