rs10972587

chr9-368030-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_203447.4(DOCK8):c.1692T>C(p.Tyr564=) 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:4
• Conservation: PhyloP100: 0.590

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 -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 id 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/exons	MANE	UniProt
DOCK8	NM_203447.4	c.1692T>C	p.Tyr564=	synonymous_variant	15/48	ENST00000432829.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DOCK8	ENST00000432829.7	c.1692T>C	p.Tyr564=	synonymous_variant	15/48	1	NM_203447.4

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

GnomAD3 exomes AF: 0.0564 AC: 14170 AN: 251310 Hom.: 1285 AF XY: 0.0497 AC XY: 6747 AN XY: 135818

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 SAS exome AF: 0.0281

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

Gnomad4 AFR exome AF: 0.364

Gnomad4 AMR exome AF: 0.0464

Gnomad4 ASJ exome AF: 0.0608

Gnomad4 EAS exome AF: 0.000831

Gnomad4 SAS exome AF: 0.0278

Gnomad4 FIN exome AF: 0.0270

Gnomad4 NFE exome AF: 0.0362

Gnomad4 OTH exome AF: 0.0514

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

Gnomad4 AFR AF: 0.359

Gnomad4 AMR AF: 0.0574

Gnomad4 ASJ AF: 0.0654

Gnomad4 EAS AF: 0.000771

Gnomad4 SAS AF: 0.0269

Gnomad4 FIN AF: 0.0250

Gnomad4 NFE AF: 0.0376

Gnomad4 OTH AF: 0.0998

Alfa AF: 0.0643 Hom.: 1186

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:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 11, 2014	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. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	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

Benign, 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 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. -

Autosomal recessive hyper-IgE syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
Cadd	Benign	3.1
Dann	Benign	0.52
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs10972587; hg19: chr9-368030;