rs111535933

Variant names:

• chr9-439352-A-G
• rs111535933
• NM_203447.4:c.5187A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_203447.4(DOCK8):​c.5187A>G​(p.Val1729Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00374 in 1,613,776 control chromosomes in the GnomAD database, including 135 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0055 (10 hom., cov: 32)
  • Exomes 𝑓: 0.0036 (125 hom.)
• Consequence: DOCK8 NM_203447.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.27
• Publications: 3 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 9-439352-A-G is Benign according to our data. Variant chr9-439352-A-G is described in ClinVar as Benign. ClinVar VariationId is 137149.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.27 with no splicing effect.
• BA1: GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0503 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.5187A>G	p.Val1729Val	synonymous	Exon 40 of 48	NP_982272.2	Q8NF50-1
	DOCK8	NM_001193536.2		c.4983A>G	p.Val1661Val	synonymous	Exon 39 of 47	NP_001180465.1	Q8NF50-3
	DOCK8	NM_001190458.2		c.4887A>G	p.Val1629Val	synonymous	Exon 38 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.5187A>G	p.Val1729Val	synonymous	Exon 40 of 48	ENSP00000394888.3	Q8NF50-1
	DOCK8	ENST00000469391.5	TSL:1	c.4887A>G	p.Val1629Val	synonymous	Exon 38 of 46	ENSP00000419438.1	Q8NF50-4
	DOCK8	ENST00000382329.2	TSL:1	c.4887A>G	p.Val1629Val	synonymous	Exon 39 of 46	ENSP00000371766.2	A2A369

Frequencies

GnomAD3 genomes AF: 0.00546 AC: 830 AN: 151876 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.00223

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0306

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.0377

Gnomad SAS AF: 0.00374

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000485

Gnomad OTH AF: 0.00718

GnomAD2 exomes AF: 0.0111 AC: 2782 AN: 251280 AF XY: 0.00915

Gnomad AFR exome AF: 0.00166

Gnomad AMR exome AF: 0.0554

Gnomad ASJ exome AF: 0.00427

Gnomad EAS exome AF: 0.0338

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000414

Gnomad OTH exome AF: 0.00603

GnomAD4 exome AF: 0.00356 AC: 5211 AN: 1461782 Hom.: 125 Cov.: 32 AF XY: 0.00329 AC XY: 2391 AN XY: 727184

African (AFR) AF: 0.00182 AC: 61 AN: 33480

American (AMR) AF: 0.0521 AC: 2330 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00394 AC: 103 AN: 26134

East Asian (EAS) AF: 0.0432 AC: 1714 AN: 39700

South Asian (SAS) AF: 0.00314 AC: 271 AN: 86256

European-Finnish (FIN) AF: 0.0000375 AC: 2 AN: 53320

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5764

European-Non Finnish (NFE) AF: 0.000400 AC: 445 AN: 1112012

Other (OTH) AF: 0.00464 AC: 280 AN: 60394

GnomAD4 genome AF: 0.00547 AC: 832 AN: 151994 Hom.: 10 Cov.: 32 AF XY: 0.00595 AC XY: 442 AN XY: 74272

African (AFR) AF: 0.00224 AC: 93 AN: 41454

American (AMR) AF: 0.0307 AC: 468 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.00346 AC: 12 AN: 3464

East Asian (EAS) AF: 0.0377 AC: 194 AN: 5140

South Asian (SAS) AF: 0.00375 AC: 18 AN: 4804

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10588

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

European-Non Finnish (NFE) AF: 0.000486 AC: 33 AN: 67966

Other (OTH) AF: 0.00664 AC: 14 AN: 2110

Alfa AF: 0.00195 Hom.: 0

Bravo AF: 0.00852

Asia WGS AF: 0.0210 AC: 72 AN: 3478

EpiCase AF: 0.000436

EpiControl AF: 0.000830

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	7.5
DANN	Benign	0.75
PhyloP100		1.3
Mutation Taster		=96/4	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: rs111535933; hg19: chr9-439352;