rs77399114

Variant names:

• chr9-414816-A-G
• rs77399114
• NM_203447.4:c.3565A>G
• DOCK8 p.Ile1189Val

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.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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I1189F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.019 (110 hom., cov: 33)
  • Exomes 𝑓: 0.0021 (86 hom.)
• Consequence: DOCK8 NM_203447.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 3.17
• Publications: 5 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, G2P, Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen
• 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=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/Likely_benign. ClinVar VariationId is 137147.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0655 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.3565A>G	p.Ile1189Val	missense	Exon 29 of 48	NP_982272.2	Q8NF50-1
	DOCK8	NM_001193536.2		c.3361A>G	p.Ile1121Val	missense	Exon 28 of 47	NP_001180465.1	Q8NF50-3
	DOCK8	NM_001190458.2		c.3265A>G	p.Ile1089Val	missense	Exon 27 of 46	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.3565A>G	p.Ile1189Val	missense	Exon 29 of 48	ENSP00000394888.3	Q8NF50-1
	DOCK8	ENST00000469391.5	TSL:1	c.3265A>G	p.Ile1089Val	missense	Exon 27 of 46	ENSP00000419438.1	Q8NF50-4
	DOCK8	ENST00000382329.2	TSL:1	c.3265A>G	p.Ile1089Val	missense	Exon 28 of 46	ENSP00000371766.2	A2A369

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

GnomAD2 exomes AF: 0.00559 AC: 1405 AN: 251464 AF XY: 0.00425

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 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

African (AFR) AF: 0.0701 AC: 2346 AN: 33480

American (AMR) AF: 0.00407 AC: 182 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00260 AC: 68 AN: 26136

East Asian (EAS) AF: 0.000227 AC: 9 AN: 39700

South Asian (SAS) AF: 0.000394 AC: 34 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00243 AC: 14 AN: 5768

European-Non Finnish (NFE) AF: 0.000192 AC: 214 AN: 1112006

Other (OTH) AF: 0.00404 AC: 244 AN: 60396

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

African (AFR) AF: 0.0676 AC: 2808 AN: 41552

American (AMR) AF: 0.00497 AC: 76 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000353 AC: 24 AN: 68012

Other (OTH) AF: 0.0137 AC: 29 AN: 2114

Alfa AF: 0.00755 Hom.: 73

Bravo AF: 0.0225

Asia WGS AF: 0.00635 AC: 22 AN: 3478

EpiCase AF: 0.000436

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	not provided (2)
-	-	1	Combined immunodeficiency due to DOCK8 deficiency (1)
-	-	1	Not specified (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.25
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.62	T
MetaRNN	Benign	0.0027	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N
PhyloP100		3.2
PrimateAI	Benign	0.38	T
PROVEAN	Benign	0.090	N
REVEL	Benign	0.053
Sift	Benign	0.96	T
Sift4G	Benign	0.83	T
Varity_R		0.017
gMVP		0.098
Mutation Taster		=98/2	polymorphism (auto)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs77399114;

hg19: chr9-414816;