rs10970979

Variant names:

• chr9-334337-A-G
• rs10970979
• NM_203447.4:c.1238A>G

Your query was ambiguous. Multiple possible variants found:

• chr9-334337-A-G
• chr9-334337-A-T

Variant summary

Our verdict is Benign. The variant received -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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N413G) has been classified as Uncertain significance.

• 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
• Publications: 33 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 -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 VariationId is 163174.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
DOCK8	NM_203447.4	c.1238A>G	p.Asn413Ser	missense_variant	Exon 11 of 48	ENST00000432829.7	NP_982272.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DOCK8	ENST00000432829.7	c.1238A>G	p.Asn413Ser	missense_variant	Exon 11 of 48	1	NM_203447.4	ENSP00000394888.3

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

GnomAD2 exomes AF: 0.245 AC: 61474 AN: 251170 AF XY: 0.252

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 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

African (AFR) AF: 0.215 AC: 7203 AN: 33476

American (AMR) AF: 0.158 AC: 7044 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.332 AC: 8684 AN: 26132

East Asian (EAS) AF: 0.0288 AC: 1142 AN: 39700

South Asian (SAS) AF: 0.258 AC: 22287 AN: 86252

European-Finnish (FIN) AF: 0.220 AC: 11767 AN: 53416

Middle Eastern (MID) AF: 0.327 AC: 1882 AN: 5762

European-Non Finnish (NFE) AF: 0.308 AC: 342489 AN: 1111808

Other (OTH) AF: 0.278 AC: 16777 AN: 60394

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

African (AFR) AF: 0.224 AC: 9307 AN: 41458

American (AMR) AF: 0.211 AC: 3231 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.325 AC: 1130 AN: 3472

East Asian (EAS) AF: 0.0331 AC: 171 AN: 5164

South Asian (SAS) AF: 0.258 AC: 1244 AN: 4822

European-Finnish (FIN) AF: 0.208 AC: 2195 AN: 10576

Middle Eastern (MID) AF: 0.330 AC: 97 AN: 294

European-Non Finnish (NFE) AF: 0.303 AC: 20601 AN: 67976

Other (OTH) AF: 0.267 AC: 564 AN: 2110

Alfa AF: 0.285 Hom.: 21139

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

Feb 21, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 12, 2023

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

-

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

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. -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Combined immunodeficiency due to DOCK8 deficiency Benign:2

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. -

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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
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;.;.
PhyloP100		-0.0080
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
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs10970979; hg19: chr9-334337; COSMIC: COSV66634249;