rs10972587

Variant names:

• chr9-368030-T-C
• rs10972587
• NM_203447.4:c.1692T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_203447.4(DOCK8):​c.1692T>C​(p.Tyr564Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0511 in 1,613,388 control chromosomes in the GnomAD database, including 6,115 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (2819 hom., cov: 32)
  • Exomes 𝑓: 0.043 (3296 hom.)
• Consequence: DOCK8 NM_203447.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.590
• Publications: 9 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

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 9-368030-T-C is Benign according to our data. Variant chr9-368030-T-C is described in ClinVar as Benign. ClinVar VariationId is 137135.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.59 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.355 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DOCK8	NM_203447.4	c.1692T>C	p.Tyr564Tyr	synonymous_variant	Exon 15 of 48	ENST00000432829.7	NP_982272.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DOCK8	ENST00000432829.7	c.1692T>C	p.Tyr564Tyr	synonymous_variant	Exon 15 of 48	1	NM_203447.4	ENSP00000394888.3

Frequencies

GnomAD3 genomes AF: 0.126 AC: 19242 AN: 152122 Hom.: 2808 Cov.: 32

Gnomad AFR AF: 0.359

Gnomad AMI AF: 0.106

Gnomad AMR AF: 0.0574

Gnomad ASJ AF: 0.0654

Gnomad EAS AF: 0.000769

Gnomad SAS AF: 0.0269

Gnomad FIN AF: 0.0250

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0376

Gnomad OTH AF: 0.0999

GnomAD2 exomes AF: 0.0564 AC: 14170 AN: 251310 AF XY: 0.0497

Gnomad AFR exome AF: 0.366

Gnomad AMR exome AF: 0.0450

Gnomad ASJ exome AF: 0.0618

Gnomad EAS exome AF: 0.000816

Gnomad FIN exome AF: 0.0260

Gnomad NFE exome AF: 0.0382

Gnomad OTH exome AF: 0.0416

GnomAD4 exome AF: 0.0433 AC: 63218 AN: 1461148 Hom.: 3296 Cov.: 30 AF XY: 0.0418 AC XY: 30414 AN XY: 726942

African (AFR) AF: 0.364 AC: 12169 AN: 33430

American (AMR) AF: 0.0464 AC: 2074 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0608 AC: 1588 AN: 26128

East Asian (EAS) AF: 0.000831 AC: 33 AN: 39698

South Asian (SAS) AF: 0.0278 AC: 2394 AN: 86248

European-Finnish (FIN) AF: 0.0270 AC: 1444 AN: 53420

Middle Eastern (MID) AF: 0.0291 AC: 168 AN: 5764

European-Non Finnish (NFE) AF: 0.0362 AC: 40246 AN: 1111370

Other (OTH) AF: 0.0514 AC: 3102 AN: 60370

GnomAD4 genome AF: 0.127 AC: 19291 AN: 152240 Hom.: 2819 Cov.: 32 AF XY: 0.123 AC XY: 9154 AN XY: 74460

African (AFR) AF: 0.359 AC: 14911 AN: 41496

American (AMR) AF: 0.0574 AC: 878 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0654 AC: 227 AN: 3470

East Asian (EAS) AF: 0.000771 AC: 4 AN: 5188

South Asian (SAS) AF: 0.0269 AC: 130 AN: 4824

European-Finnish (FIN) AF: 0.0250 AC: 265 AN: 10620

Middle Eastern (MID) AF: 0.0374 AC: 11 AN: 294

European-Non Finnish (NFE) AF: 0.0376 AC: 2558 AN: 68026

Other (OTH) AF: 0.0998 AC: 210 AN: 2104

Alfa AF: 0.0721 Hom.: 1769

Bravo AF: 0.139

Asia WGS AF: 0.0320 AC: 111 AN: 3478

EpiCase AF: 0.0365

EpiControl AF: 0.0324

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Mar 11, 2014

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Feb 21, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Tyr564Tyr in exon 15 of DOCK8: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue and is not located wit hin the splice consensus sequence. It has been identified in 36.0% (1584/4406) o f African American chromosomes from a broad population by the NHLBI Exome Sequen cing Project (http://evs.gs.washington.edu/EVS; dbSNP rs10972587). -

Combined immunodeficiency due to DOCK8 deficiency Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	3.1
DANN	Benign	0.52
PhyloP100		0.59
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs10972587; hg19: chr9-368030;