9-439352-A-G

Position:

• chr9-439352-A-G

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.5187A>G​(p.Val1729=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00374 in 1,613,776 control chromosomes in the GnomAD database, including 135 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0055 (10 hom., cov: 32)
  • Exomes 𝑓: 0.0036 (125 hom.)
• Consequence: DOCK8 NM_203447.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.27

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=-0.5).
• BP6: Variant 9-439352-A-G is Benign according to our data. Variant chr9-439352-A-G is described in ClinVar as [Benign]. Clinvar id is 137149.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.27 with no splicing effect.
• BA1: GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0503 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DOCK8	NM_203447.4	c.5187A>G	p.Val1729=	synonymous_variant	40/48	ENST00000432829.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DOCK8	ENST00000432829.7	c.5187A>G	p.Val1729=	synonymous_variant	40/48	1	NM_203447.4

Frequencies

GnomAD3 genomes AF: 0.00546 AC: 830 AN: 151876 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.00223

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0306

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.0377

Gnomad SAS AF: 0.00374

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000485

Gnomad OTH AF: 0.00718

GnomAD3 exomes AF: 0.0111 AC: 2782 AN: 251280 Hom.: 71 AF XY: 0.00915 AC XY: 1243 AN XY: 135820

Gnomad AFR exome AF: 0.00166

Gnomad AMR exome AF: 0.0554

Gnomad ASJ exome AF: 0.00427

Gnomad EAS exome AF: 0.0338

Gnomad SAS exome AF: 0.00294

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000414

Gnomad OTH exome AF: 0.00603

GnomAD4 exome AF: 0.00356 AC: 5211 AN: 1461782 Hom.: 125 Cov.: 32 AF XY: 0.00329 AC XY: 2391 AN XY: 727184

Gnomad4 AFR exome AF: 0.00182

Gnomad4 AMR exome AF: 0.0521

Gnomad4 ASJ exome AF: 0.00394

Gnomad4 EAS exome AF: 0.0432

Gnomad4 SAS exome AF: 0.00314

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.000400

Gnomad4 OTH exome AF: 0.00464

GnomAD4 genome AF: 0.00547 AC: 832 AN: 151994 Hom.: 10 Cov.: 32 AF XY: 0.00595 AC XY: 442 AN XY: 74272

Gnomad4 AFR AF: 0.00224

Gnomad4 AMR AF: 0.0307

Gnomad4 ASJ AF: 0.00346

Gnomad4 EAS AF: 0.0377

Gnomad4 SAS AF: 0.00375

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000486

Gnomad4 OTH AF: 0.00664

Alfa AF: 0.00195 Hom.: 0

Bravo AF: 0.00852

Asia WGS AF: 0.0210 AC: 72 AN: 3478

EpiCase AF: 0.000436

EpiControl AF: 0.000830

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive hyper-IgE syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Combined immunodeficiency due to DOCK8 deficiency Benign:1

Benign, 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 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 specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 06, 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. -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	7.5
DANN	Benign	0.75

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: rs111535933; hg19: chr9-439352;