9-334337-A-G

Position:

• chr9-334337-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.1238A>G​(p.Asn413Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.284 in 1,613,726 control chromosomes in the GnomAD database, including 67,987 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 0.26 (5110 hom., cov: 32)
  • Exomes 𝑓: 0.29 (62877 hom.)
• Consequence: DOCK8 NM_203447.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8 O:1
• Conservation: PhyloP100: -0.00800

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=9.584427E-4).
• BP6: Variant 9-334337-A-G is Benign according to our data. Variant chr9-334337-A-G is described in ClinVar as [Benign]. Clinvar id is 163174.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-334337-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.3 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DOCK8	NM_203447.4	c.1238A>G	p.Asn413Ser	missense_variant	11/48	ENST00000432829.7	NP_982272.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DOCK8	ENST00000432829.7	c.1238A>G	p.Asn413Ser	missense_variant	11/48	1	NM_203447.4	ENSP00000394888

Frequencies

GnomAD3 genomes AF: 0.256 AC: 38838 AN: 151950 Hom.: 5106 Cov.: 32

Gnomad AFR AF: 0.225

Gnomad AMI AF: 0.339

Gnomad AMR AF: 0.212

Gnomad ASJ AF: 0.325

Gnomad EAS AF: 0.0328

Gnomad SAS AF: 0.257

Gnomad FIN AF: 0.208

Gnomad MID AF: 0.332

Gnomad NFE AF: 0.303

Gnomad OTH AF: 0.271

GnomAD3 exomes AF: 0.245 AC: 61474 AN: 251170 Hom.: 8478 AF XY: 0.252 AC XY: 34160 AN XY: 135734

Gnomad AFR exome AF: 0.219

Gnomad AMR exome AF: 0.153

Gnomad ASJ exome AF: 0.333

Gnomad EAS exome AF: 0.0319

Gnomad SAS exome AF: 0.262

Gnomad FIN exome AF: 0.217

Gnomad NFE exome AF: 0.303

Gnomad OTH exome AF: 0.266

GnomAD4 exome AF: 0.287 AC: 419275 AN: 1461658 Hom.: 62877 Cov.: 36 AF XY: 0.287 AC XY: 208450 AN XY: 727122

Gnomad4 AFR exome AF: 0.215

Gnomad4 AMR exome AF: 0.158

Gnomad4 ASJ exome AF: 0.332

Gnomad4 EAS exome AF: 0.0288

Gnomad4 SAS exome AF: 0.258

Gnomad4 FIN exome AF: 0.220

Gnomad4 NFE exome AF: 0.308

Gnomad4 OTH exome AF: 0.278

GnomAD4 genome AF: 0.255 AC: 38849 AN: 152068 Hom.: 5110 Cov.: 32 AF XY: 0.249 AC XY: 18505 AN XY: 74330

Gnomad4 AFR AF: 0.224

Gnomad4 AMR AF: 0.211

Gnomad4 ASJ AF: 0.325

Gnomad4 EAS AF: 0.0331

Gnomad4 SAS AF: 0.258

Gnomad4 FIN AF: 0.208

Gnomad4 NFE AF: 0.303

Gnomad4 OTH AF: 0.267

Alfa AF: 0.289 Hom.: 15882

Bravo AF: 0.252

ESP6500AA AF: 0.229 AC: 1009

ESP6500EA AF: 0.309 AC: 2659

ExAC AF: 0.249 AC: 30196

Asia WGS AF: 0.135 AC: 472 AN: 3476

EpiCase AF: 0.308

EpiControl AF: 0.313

ClinVar

Significance: Benign

Submissions summary: Benign:8 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	Asn413Ser in exon 11 of DOCK8: This variant is not expected to have clinical sig nificance because it has been identified in 30.9% (2659/8600) of European Americ an chromosomes from a broad population by the NHLBI Exome Sequencing Project (ht tp://evs.gs.washington.edu/EVS; dbSNP rs10970979). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Nov 12, 2023	This variant is classified as Benign based on local population frequency. This variant was detected in 34% of patients studied by a panel of primary immunodeficiencies. Number of patients: 33. Only high quality variants are reported. -

not provided Benign:2 Other:1

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	Variant interpreted as Benign and reported on 04-27-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. This variant was reported in an individual referred for clinical diagnostic genetic testing. -

Combined immunodeficiency due to DOCK8 deficiency Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -

Autosomal recessive hyper-IgE syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.051
BayesDel_addAF	Benign	-0.76	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	1.2
DANN	Benign	0.90
DEOGEN2	Benign	0.087	T;.;.
Eigen	Benign	-0.90
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.75	T;T;T
MetaRNN	Benign	0.00096	T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.33	N;.;.
MutationTaster	Benign	0.029	P;P;P
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.88	.;.;N
REVEL	Benign	0.056
Sift	Benign	0.44	.;.;T
Sift4G	Benign	0.64	T;T;T
Polyphen		0.0	B;.;.
Vest4		0.031
MPC		0.037
ClinPred		0.0034	T
GERP RS		2.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.023
gMVP		0.089

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs10970979; hg19: chr9-334337; COSMIC: COSV66634249;