rs73382631

Variant names:

• chr9-399233-A-G
• rs73382631
• NM_203447.4:c.3208A>G

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.3208A>G​(p.Asn1070Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0062 in 1,613,616 control chromosomes in the GnomAD database, including 476 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N1070S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.030 (224 hom., cov: 32)
  • Exomes 𝑓: 0.0037 (252 hom.)
• Consequence: DOCK8 NM_203447.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 2.30
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0033479035).
• BP6: Variant 9-399233-A-G is Benign according to our data. Variant chr9-399233-A-G is described in ClinVar as Benign. ClinVar VariationId is 137143.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.101 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.3208A>G	p.Asn1070Asp	missense	Exon 26 of 48	NP_982272.2	Q8NF50-1
	DOCK8	NM_001193536.2		c.3004A>G	p.Asn1002Asp	missense	Exon 25 of 47	NP_001180465.1	Q8NF50-3
	DOCK8	NM_001190458.2		c.2908A>G	p.Asn970Asp	missense	Exon 24 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.3208A>G	p.Asn1070Asp	missense	Exon 26 of 48	ENSP00000394888.3	Q8NF50-1
	DOCK8	ENST00000469391.5	TSL:1	c.2908A>G	p.Asn970Asp	missense	Exon 24 of 46	ENSP00000419438.1	Q8NF50-4
	DOCK8	ENST00000382329.2	TSL:1	c.2908A>G	p.Asn970Asp	missense	Exon 25 of 46	ENSP00000371766.2	A2A369

Frequencies

GnomAD3 genomes AF: 0.0302 AC: 4588 AN: 151822 Hom.: 223 Cov.: 32

Gnomad AFR AF: 0.104

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0150

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.000603

Gnomad OTH AF: 0.0192

GnomAD2 exomes AF: 0.00837 AC: 2101 AN: 251048 AF XY: 0.00612

Gnomad AFR exome AF: 0.110

Gnomad AMR exome AF: 0.00503

Gnomad ASJ exome AF: 0.00149

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000741

Gnomad OTH exome AF: 0.00473

GnomAD4 exome AF: 0.00369 AC: 5389 AN: 1461678 Hom.: 252 Cov.: 32 AF XY: 0.00326 AC XY: 2368 AN XY: 727118

African (AFR) AF: 0.114 AC: 3808 AN: 33468

American (AMR) AF: 0.00662 AC: 296 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00134 AC: 35 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

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

European-Finnish (FIN) AF: 0.0000563 AC: 3 AN: 53302

Middle Eastern (MID) AF: 0.0172 AC: 99 AN: 5766

European-Non Finnish (NFE) AF: 0.000508 AC: 565 AN: 1111948

Other (OTH) AF: 0.00909 AC: 549 AN: 60384

GnomAD4 genome AF: 0.0304 AC: 4612 AN: 151938 Hom.: 224 Cov.: 32 AF XY: 0.0292 AC XY: 2167 AN XY: 74326

African (AFR) AF: 0.104 AC: 4292 AN: 41304

American (AMR) AF: 0.0150 AC: 229 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4808

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10592

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.000603 AC: 41 AN: 67996

Other (OTH) AF: 0.0190 AC: 40 AN: 2106

Alfa AF: 0.0240 Hom.: 167

Bravo AF: 0.0363

ESP6500AA AF: 0.106 AC: 468

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.0102 AC: 1243

Asia WGS AF: 0.0130 AC: 45 AN: 3478

EpiCase AF: 0.000545

EpiControl AF: 0.00107

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	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
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.029
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.94	D
MetaRNN	Benign	0.0033	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		2.3
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.10
Sift	Benign	0.093	T
Sift4G	Benign	0.31	T
Polyphen		0.0	B
Vest4		0.44
MPC		0.051
ClinPred		0.018	T
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.14
gMVP		0.43
Mutation Taster		=94/6	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: rs73382631; hg19: chr9-399233;