chr9-331490-T-G

Variant names:

• chr9-331490-T-G
• rs10813766
• NM_203447.4:c.1045-908T>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.1045-908T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.64 in 152,120 control chromosomes in the GnomAD database, including 31,363 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 0.64 (31363 hom., cov: 33)
• Consequence: DOCK8 NM_203447.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.987
• Publications: 20 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: Ambry Genetics, Genomics England PanelApp, ClinGen, Orphanet, Labcorp Genetics (formerly Invitae), G2P
• 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=-0.82).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.737 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_203447.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DOCK8	NM_203447.4	MANE Select	c.1045-908T>G		intron	N/A	NP_982272.2	Q8NF50-1
	DOCK8	NM_001193536.2		c.841-908T>G		intron	N/A	NP_001180465.1	Q8NF50-3
	DOCK8	NM_001190458.2		c.841-908T>G		intron	N/A	NP_001177387.1	Q8NF50-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DOCK8	ENST00000432829.7	TSL:1 MANE Select	c.1045-908T>G		intron	N/A	ENSP00000394888.3	Q8NF50-1
	DOCK8	ENST00000469391.5	TSL:1	c.841-908T>G		intron	N/A	ENSP00000419438.1	Q8NF50-4
	DOCK8	ENST00000382329.2	TSL:1	c.841-908T>G		intron	N/A	ENSP00000371766.2	A2A369

Frequencies

GnomAD3 genomes AF: 0.641 AC: 97375 AN: 152002 Hom.: 31355 Cov.: 33

Gnomad AFR AF: 0.606

Gnomad AMI AF: 0.779

Gnomad AMR AF: 0.631

Gnomad ASJ AF: 0.534

Gnomad EAS AF: 0.711

Gnomad SAS AF: 0.758

Gnomad FIN AF: 0.652

Gnomad MID AF: 0.513

Gnomad NFE AF: 0.653

Gnomad OTH AF: 0.613

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

GnomAD4 genome AF: 0.640 AC: 97411 AN: 152120 Hom.: 31363 Cov.: 33 AF XY: 0.643 AC XY: 47778 AN XY: 74352

African (AFR) AF: 0.605 AC: 25112 AN: 41496

American (AMR) AF: 0.631 AC: 9659 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.534 AC: 1854 AN: 3472

East Asian (EAS) AF: 0.711 AC: 3678 AN: 5170

South Asian (SAS) AF: 0.757 AC: 3651 AN: 4820

European-Finnish (FIN) AF: 0.652 AC: 6901 AN: 10580

Middle Eastern (MID) AF: 0.517 AC: 152 AN: 294

European-Non Finnish (NFE) AF: 0.653 AC: 44391 AN: 67972

Other (OTH) AF: 0.618 AC: 1303 AN: 2108

Alfa AF: 0.646 Hom.: 134453

Bravo AF: 0.634

Asia WGS AF: 0.732 AC: 2544 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	4.2
DANN	Benign	0.82
PhyloP100		0.99
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: rs10813766; hg19: chr9-331490;