NM_203447.4:c.54-1G>T

Variant names:

• chr9-271626-G-T
• rs192864327
• NM_203447.4:c.54-1G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PVS1 PP5

The NM_203447.4(DOCK8):​c.54-1G>T variant causes a splice acceptor, intron change. The variant allele was found at a frequency of 0.000619 in 1,539,240 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00035 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00065 (0 hom.)
• Consequence: DOCK8 NM_203447.4 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:13 U:3
• Conservation: PhyloP100: 5.96
• Publications: 4 publications found

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 Gene-Disease associations (from GenCC):

• combined immunodeficiency due to DOCK8 deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: Orphanet, ClinGen, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, Genomics England PanelApp
• autosomal dominant non-syndromic intellectual disability

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• complex neurodevelopmental disorder

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ENSG00000235880 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 4.1, offset of 11, new splice context is: taatccaatgtattcttcAGcgg. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PP5: Variant 9-271626-G-T is Pathogenic according to our data. Variant chr9-271626-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 265359.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DOCK8	NM_203447.4	c.54-1G>T		splice_acceptor_variant, intron_variant	Intron 1 of 47	ENST00000432829.7	NP_982272.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DOCK8	ENST00000432829.7	c.54-1G>T		splice_acceptor_variant, intron_variant	Intron 1 of 47	1	NM_203447.4	ENSP00000394888.3

Frequencies

GnomAD3 genomes AF: 0.000349 AC: 53 AN: 152078 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000632

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000263 AC: 41 AN: 155748 AF XY: 0.000279

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000411

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000597

Gnomad NFE exome AF: 0.000479

Gnomad OTH exome AF: 0.000229

GnomAD4 exome AF: 0.000649 AC: 900 AN: 1387162 Hom.: 0 Cov.: 28 AF XY: 0.000641 AC XY: 439 AN XY: 684950

African (AFR) AF: 0.0000319 AC: 1 AN: 31380

American (AMR) AF: 0.000507 AC: 18 AN: 35472

Ashkenazi Jewish (ASJ) AF: 0.0000398 AC: 1 AN: 25110

East Asian (EAS) AF: 0.00 AC: 0 AN: 35608

South Asian (SAS) AF: 0.00 AC: 0 AN: 78824

European-Finnish (FIN) AF: 0.0000203 AC: 1 AN: 49160

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5678

European-Non Finnish (NFE) AF: 0.000782 AC: 835 AN: 1068324

Other (OTH) AF: 0.000764 AC: 44 AN: 57606

GnomAD4 genome AF: 0.000349 AC: 53 AN: 152078 Hom.: 0 Cov.: 33 AF XY: 0.000417 AC XY: 31 AN XY: 74280

African (AFR) AF: 0.0000483 AC: 2 AN: 41392

American (AMR) AF: 0.000458 AC: 7 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10594

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000632 AC: 43 AN: 68020

Other (OTH) AF: 0.000478 AC: 1 AN: 2090

Alfa AF: 0.000530 Hom.: 0

Bravo AF: 0.000442

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.000121 AC: 3

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:13 Uncertain:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Combined immunodeficiency due to DOCK8 deficiency Pathogenic:7

Feb 01, 2019

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -

Dec 05, 2022

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 25, 2018

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1,PM2. -

-

UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

The DOCK8 c.54-1G>T (p.?) variant is predicted to alter a canonical splice site. -

Mar 30, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Mar 12, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 16, 2024

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: DOCK8 c.54-1G>T is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 3' acceptor site, expected to cause altered splicing of exon 2 (deletion of exon 2 has been reported in patients with DOCK8 deficiency [PMID: 25724123]). However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00062 in 1539240 control chromosomes (gnomAD). c.54-1G>T has been reported in a homozygous patient with albinism, neutropenia and immunodeficiency, neurodevelopmental delay, generalized seizures and impaired hearing; however, this patient was also homozygous for AP3D1 c.3565_3566delGT (p.Val1189LeufsX8) which may explain the patients phenotype (Ammann_2016). This report does not provide unequivocal conclusions about association of the variant with Combined Immunodeficiency Due To DOCK8 Deficiency. 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: 26744459, 37592284, 31980526). ClinVar contains an entry for this variant (Variation ID: 265359). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

not provided Pathogenic:4 Uncertain:1

Apr 16, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP3 -

Aug 02, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 31589614, 31980526, 26744459, 26689913) -

Jun 14, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

DOCK8-related disorder Pathogenic:1

Nov 09, 2023

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The DOCK8 c.54-1G>T variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. To our knowledge, this variant has not been reported in the literature in individuals with DOCK8-associated disease. However, variants that disrupt the consensus AG acceptor site in DOCK8 are expected to be pathogenic. Other DOCK8 splicing, nonsense and frameshift variants have been reported as pathogenic downstream of this variant (Human Gene Mutation Database, HGMD). At least one pathogenic gross deletion encompassing DOCK8 exon 1 has also been reported upstream of this variant (Engelhardt et al. 2015. PubMed ID: 25724123). This variant is interpreted as likely pathogenic. -

Pathogenic:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects an acceptor splice site in intron 1 of the DOCK8 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in DOCK8 are known to be pathogenic (PMID: 14722525, 19776401). This variant is present in population databases (rs192864327, gnomAD 0.05%). 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: 265359). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

not specified Uncertain:1

Oct 08, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

Variant classified as Uncertain Significance - Favor Pathogenic. The c.54-1G>T v ariant in DOCK8 has been reported in the homozygous state in one Turkish child w ith albinism, neutropenia, immunodeficiency, neurodevelopmental delay, generaliz ed seizures, and impaired hearing (Ammann 2016); however, this individual also h ad a homozyous variant in the AP3D1 gene (p.Val1189LeufsX8) that may explain his clinical presentation. The c.54-1G>T variant has been identified in 0.05% (35/7 2808) of European chromosomes by the Genome Aggregation Database (gnomAD, http:/ /gnomad.broadinstitute.org), and has been reported in ClinVar (Variation ID 2653 59). This variant occurs in the invariant region (+/- 1,2) of the splice consens us sequence and is predicted to cause altered splicing of DOCK8 exon 2, which is unique to NM_203447.3. While transcript NM_203447.3 is expressed across adult a nd fetal tissues (Griggs 2008) and DOCK8 deficiency patients with exon 2 deletio n have been reported in the literature (Engelhardt 2015), the impact of the loss of this transcript is unclear. Therefore, the impact of this variant on DOCK8 f unction is unclear. In summary, while there is some suspicion for a pathogenic r ole, given the presence of conflicting data, the clinical significance of the c. 54-1G>T variant is uncertain. ACMG/AMP Criteria applied: PP3, PM2_Supporting. -

Intellectual disability Uncertain:1

Jan 01, 2019

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.23
CADD	Pathogenic	31
DANN	Uncertain	0.99
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Uncertain	0.86	D
PhyloP100		6.0
GERP RS		5.9
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.95		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.95		Position offset: 1

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

Other links and lift over

dbSNP: rs192864327; hg19: chr9-271626;