rs6476030

Variant names:

• chr9-289061-A-G
• rs6476030
• NM_203447.4:c.333-449A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_203447.4(DOCK8):​c.333-449A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0687 in 152,278 control chromosomes in the GnomAD database, including 618 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.069 (618 hom., cov: 33)
• Consequence: DOCK8 NM_203447.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.830
• Publications: 9 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.159 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DOCK8	NM_203447.4	c.333-449A>G		intron_variant	Intron 3 of 47	ENST00000432829.7	NP_982272.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DOCK8	ENST00000432829.7	c.333-449A>G		intron_variant	Intron 3 of 47	1	NM_203447.4	ENSP00000394888.3

Frequencies

GnomAD3 genomes AF: 0.0686 AC: 10431 AN: 152160 Hom.: 614 Cov.: 33

Gnomad AFR AF: 0.162

Gnomad AMI AF: 0.121

Gnomad AMR AF: 0.0693

Gnomad ASJ AF: 0.0374

Gnomad EAS AF: 0.0164

Gnomad SAS AF: 0.0333

Gnomad FIN AF: 0.0143

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0279

Gnomad OTH AF: 0.0588

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0687 AC: 10459 AN: 152278 Hom.: 618 Cov.: 33 AF XY: 0.0663 AC XY: 4934 AN XY: 74472

African (AFR) AF: 0.162 AC: 6734 AN: 41526

American (AMR) AF: 0.0692 AC: 1059 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0374 AC: 130 AN: 3472

East Asian (EAS) AF: 0.0164 AC: 85 AN: 5186

South Asian (SAS) AF: 0.0334 AC: 161 AN: 4826

European-Finnish (FIN) AF: 0.0143 AC: 152 AN: 10614

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0279 AC: 1896 AN: 68036

Other (OTH) AF: 0.0591 AC: 125 AN: 2114

Alfa AF: 0.0445 Hom.: 890

Bravo AF: 0.0776

Asia WGS AF: 0.0440 AC: 156 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.81
DANN	Benign	0.68
PhyloP100		-0.83
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs6476030; hg19: chr9-289061;