rs77399114

Positions:

• chr9-414816-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_203447.4(DOCK8):​c.3565A>G​(p.Ile1189Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00375 in 1,614,158 control chromosomes in the GnomAD database, including 196 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.019 (110 hom., cov: 33)
  • Exomes 𝑓: 0.0021 (86 hom.)
• Consequence: DOCK8 NM_203447.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 3.17

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0026513338).
• BP6: Variant 9-414816-A-G is Benign according to our data. Variant chr9-414816-A-G is described in ClinVar as [Benign]. Clinvar id is 137147.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-414816-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0655 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DOCK8	NM_203447.4	c.3565A>G	p.Ile1189Val	missense_variant	29/48	ENST00000432829.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DOCK8	ENST00000432829.7	c.3565A>G	p.Ile1189Val	missense_variant	29/48	1	NM_203447.4

Frequencies

GnomAD3 genomes AF: 0.0194 AC: 2953 AN: 152154 Hom.: 110 Cov.: 33

Gnomad AFR AF: 0.0678

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00498

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000353

Gnomad OTH AF: 0.0139

GnomAD3 exomes AF: 0.00559 AC: 1405 AN: 251464 Hom.: 63 AF XY: 0.00425 AC XY: 577 AN XY: 135904

Gnomad AFR exome AF: 0.0716

Gnomad AMR exome AF: 0.00376

Gnomad ASJ exome AF: 0.00317

Gnomad EAS exome AF: 0.000381

Gnomad SAS exome AF: 0.000392

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000352

Gnomad OTH exome AF: 0.00326

GnomAD4 exome AF: 0.00213 AC: 3111 AN: 1461886 Hom.: 86 Cov.: 32 AF XY: 0.00184 AC XY: 1337 AN XY: 727246

Gnomad4 AFR exome AF: 0.0701

Gnomad4 AMR exome AF: 0.00407

Gnomad4 ASJ exome AF: 0.00260

Gnomad4 EAS exome AF: 0.000227

Gnomad4 SAS exome AF: 0.000394

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000192

Gnomad4 OTH exome AF: 0.00404

GnomAD4 genome AF: 0.0194 AC: 2950 AN: 152272 Hom.: 110 Cov.: 33 AF XY: 0.0184 AC XY: 1372 AN XY: 74460

Gnomad4 AFR AF: 0.0676

Gnomad4 AMR AF: 0.00497

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000353

Gnomad4 OTH AF: 0.0137

Alfa AF: 0.00362 Hom.: 21

Bravo AF: 0.0225

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0685 AC: 302

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.00689 AC: 837

Asia WGS AF: 0.00635 AC: 22 AN: 3478

EpiCase AF: 0.000436

EpiControl AF: 0.000237

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	Ile1189Val in exon 29 of DOCK8: This variant is not expected to have clinical si gnificance because it has been identified in 6.9% (302/4406) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs77399114). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 21, 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. -

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. -

Autosomal recessive hyper-IgE syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Jun 04, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	17
DANN	Benign	0.65
DEOGEN2	Benign	0.099	T;.;.;T
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.25
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.62	T;T;T;T
MetaRNN	Benign	0.0027	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N;.;.;.
MutationTaster	Benign	0.54	D;D;D;D
PrimateAI	Benign	0.38	T
REVEL	Benign	0.053
Sift4G	Benign	0.83	T;T;T;T
Polyphen		0.0080	B;.;.;B
Vest4		0.084
MVP		0.24
MPC		0.039
ClinPred		0.0013	T
GERP RS		3.7
Varity_R		0.017
gMVP		0.098

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs77399114; hg19: chr9-414816;