rs139391329

Variant names:

• chr9-312088-C-A
• rs139391329
• NM_203447.4:c.663C>A

Your query was ambiguous. Multiple possible variants found:

• chr9-312088-C-A
• chr9-312088-C-G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_203447.4(DOCK8):​c.663C>A​(p.Asp221Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00235 in 1,614,224 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0017 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0024 (9 hom.)
• Consequence: DOCK8 NM_203447.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 1.64
• Publications: 10 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004763007).
• BP6: Variant 9-312088-C-A is Benign according to our data. Variant chr9-312088-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 366546.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00169 (257/152340) while in subpopulation NFE AF = 0.00281 (191/68032). AF 95% confidence interval is 0.00248. There are 0 homozygotes in GnomAd4. There are 123 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 9 AR,AD gene

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.663C>A	p.Asp221Glu	missense	Exon 6 of 48	NP_982272.2	Q8NF50-1
	DOCK8	NM_001193536.2		c.459C>A	p.Asp153Glu	missense	Exon 5 of 47	NP_001180465.1	Q8NF50-3
	DOCK8	NM_001190458.2		c.459C>A	p.Asp153Glu	missense	Exon 5 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.663C>A	p.Asp221Glu	missense	Exon 6 of 48	ENSP00000394888.3	Q8NF50-1
	DOCK8	ENST00000469391.5	TSL:1	c.459C>A	p.Asp153Glu	missense	Exon 5 of 46	ENSP00000419438.1	Q8NF50-4
	DOCK8	ENST00000382329.2	TSL:1	c.459C>A	p.Asp153Glu	missense	Exon 6 of 46	ENSP00000371766.2	A2A369

Frequencies

GnomAD3 genomes AF: 0.00169 AC: 257 AN: 152222 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000748

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.00179

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00281

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00175 AC: 440 AN: 251414 AF XY: 0.00183

Gnomad AFR exome AF: 0.000738

Gnomad AMR exome AF: 0.000463

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00139

Gnomad NFE exome AF: 0.00255

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.00242 AC: 3542 AN: 1461884 Hom.: 9 Cov.: 31 AF XY: 0.00241 AC XY: 1750 AN XY: 727246

African (AFR) AF: 0.000418 AC: 14 AN: 33480

American (AMR) AF: 0.000402 AC: 18 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00279 AC: 241 AN: 86256

European-Finnish (FIN) AF: 0.00129 AC: 69 AN: 53420

Middle Eastern (MID) AF: 0.00225 AC: 13 AN: 5768

European-Non Finnish (NFE) AF: 0.00279 AC: 3103 AN: 1112004

Other (OTH) AF: 0.00139 AC: 84 AN: 60396

GnomAD4 genome AF: 0.00169 AC: 257 AN: 152340 Hom.: 0 Cov.: 32 AF XY: 0.00165 AC XY: 123 AN XY: 74488

African (AFR) AF: 0.000746 AC: 31 AN: 41580

American (AMR) AF: 0.000261 AC: 4 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5190

South Asian (SAS) AF: 0.00207 AC: 10 AN: 4826

European-Finnish (FIN) AF: 0.00179 AC: 19 AN: 10620

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

European-Non Finnish (NFE) AF: 0.00281 AC: 191 AN: 68032

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.00225 Hom.: 2

Bravo AF: 0.00144

TwinsUK AF: 0.00593 AC: 22

ALSPAC AF: 0.00337 AC: 13

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00291 AC: 25

ExAC AF: 0.00173 AC: 210

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00218

EpiControl AF: 0.00124

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	15
DANN	Benign	0.29
DEOGEN2	Benign	0.10	T
Eigen	Benign	-0.92
Eigen_PC	Benign	-0.68
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.0042	T
MetaRNN	Benign	0.0048	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-0.93	N
PhyloP100		1.6
PrimateAI	Benign	0.43	T
PROVEAN	Benign	0.99	N
REVEL	Benign	0.057
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.16
MutPred		0.20		Gain of helix (P = 0.0225)
MVP		0.20
MPC		0.042
ClinPred		0.0056	T
GERP RS		2.8
Varity_R		0.069
gMVP		0.23
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs139391329; hg19: chr9-312088;