rs138810908

Positions:

• chr9-404995-G-C

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Moderate BS1_Supporting BS2

The NM_203447.4(DOCK8):​c.3312G>C​(p.Glu1104Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000891 in 1,613,968 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00093 (2 hom.)
• Consequence: DOCK8 NM_203447.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:1
• Conservation: PhyloP100: -0.0640

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]

DOCK8 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.13484788).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.000928 (1357/1461768) while in subpopulation NFE AF= 0.00111 (1231/1111954). AF 95% confidence interval is 0.00106. There are 2 homozygotes in gnomad4_exome. There are 659 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DOCK8	NM_203447.4	c.3312G>C	p.Glu1104Asp	missense_variant	27/48	ENST00000432829.7	NP_982272.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DOCK8	ENST00000432829.7	c.3312G>C	p.Glu1104Asp	missense_variant	27/48	1	NM_203447.4	ENSP00000394888.3

Frequencies

GnomAD3 genomes AF: 0.000533 AC: 81 AN: 152082 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000867

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000704 AC: 177 AN: 251296 Hom.: 0 AF XY: 0.000626 AC XY: 85 AN XY: 135842

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000607

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000294

Gnomad FIN exome AF: 0.000231

Gnomad NFE exome AF: 0.00118

Gnomad OTH exome AF: 0.000979

GnomAD4 exome AF: 0.000928 AC: 1357 AN: 1461768 Hom.: 2 Cov.: 31 AF XY: 0.000906 AC XY: 659 AN XY: 727180

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.000604

Gnomad4 ASJ exome AF: 0.0000765

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000243

Gnomad4 FIN exome AF: 0.000375

Gnomad4 NFE exome AF: 0.00111

Gnomad4 OTH exome AF: 0.000878

GnomAD4 genome AF: 0.000532 AC: 81 AN: 152200 Hom.: 0 Cov.: 32 AF XY: 0.000484 AC XY: 36 AN XY: 74424

Gnomad4 AFR AF: 0.000217

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.000868

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.00106 Hom.: 0

Bravo AF: 0.000563

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.000782 AC: 95

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00104

EpiControl AF: 0.00107

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6 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	Illumina Laboratory Services, Illumina	Jan 12, 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	New York Genome Center	Jun 03, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -

not provided Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Autosomal recessive hyper-IgE syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 1104 of the DOCK8 protein (p.Glu1104Asp). This variant is present in population databases (rs138810908, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. 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: 366974). 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 expected to disrupt DOCK8 protein function with a positive 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. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jan 11, 2024

Variant summary: DOCK8 c.3312G>C (p.Glu1104Asp) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0007 in 251296 control chromosomes, predominantly at a frequency of 0.0012 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 4-fold of the estimated maximal expected allele frequency for a pathogenic variant in DOCK8 causing Severe Combined Immunodeficiency phenotype (0.00035), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.3312G>C has been reported in the literature in individuals affected with Common Variable Immunodeficiency and Autism/Developmental Delay, without strong evidence for causality (Maffucci_2016, Guo_2018). These report(s) do not provide unequivocal conclusions about association of the variant with Severe Combined Immunodeficiency. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 30564305, 27379089). ClinVar contains an entry for this variant (Variation ID: 366974, VUS). Based on the evidence outlined above, the variant was classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.61	D;.;.;T;T
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.79
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Pathogenic	1.0	D;D;D;D;D
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.13	T;T;T;T;T
MetaSVM	Benign	-0.64	T
MutationAssessor	Uncertain	2.4	M;.;.;.;.
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-2.7	.;.;D;D;D
REVEL	Uncertain	0.38
Sift	Uncertain	0.016	.;.;D;D;D
Sift4G	Uncertain	0.0050	D;D;D;D;D
Polyphen		1.0	D;.;.;D;D
Vest4		0.79
MutPred		0.50		Loss of helix (P = 0.1706);.;.;.;.;
MVP		0.40
MPC		0.29
ClinPred		0.26	T
GERP RS		-7.7
Varity_R		0.42
gMVP		0.64

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: rs138810908; hg19: chr9-404995;