rs34627722

Variant names:

• chr9-399255-G-A
• rs34627722
• NM_203447.4:c.3230G>A

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.3230G>A​(p.Ser1077Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0366 in 1,610,006 control chromosomes in the GnomAD database, including 1,682 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.056 (366 hom., cov: 32)
  • Exomes 𝑓: 0.035 (1316 hom.)
• Consequence: DOCK8 NM_203447.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 4.43
• Publications: 7 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=0.0021474957).
• BP6: Variant 9-399255-G-A is Benign according to our data. Variant chr9-399255-G-A is described in ClinVar as Benign. ClinVar VariationId is 137144.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.104 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.3230G>A	p.Ser1077Asn	missense	Exon 26 of 48	NP_982272.2	Q8NF50-1
	DOCK8	NM_001193536.2		c.3026G>A	p.Ser1009Asn	missense	Exon 25 of 47	NP_001180465.1	Q8NF50-3
	DOCK8	NM_001190458.2		c.2930G>A	p.Ser977Asn	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.3230G>A	p.Ser1077Asn	missense	Exon 26 of 48	ENSP00000394888.3	Q8NF50-1
	DOCK8	ENST00000469391.5	TSL:1	c.2930G>A	p.Ser977Asn	missense	Exon 24 of 46	ENSP00000419438.1	Q8NF50-4
	DOCK8	ENST00000382329.2	TSL:1	c.2930G>A	p.Ser977Asn	missense	Exon 25 of 46	ENSP00000371766.2	A2A369

Frequencies

GnomAD3 genomes AF: 0.0556 AC: 8375 AN: 150670 Hom.: 355 Cov.: 32

Gnomad AFR AF: 0.106

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0786

Gnomad ASJ AF: 0.0121

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0435

Gnomad FIN AF: 0.0566

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0286

Gnomad OTH AF: 0.0506

GnomAD2 exomes AF: 0.0477 AC: 11950 AN: 250630 AF XY: 0.0435

Gnomad AFR exome AF: 0.111

Gnomad AMR exome AF: 0.113

Gnomad ASJ exome AF: 0.0122

Gnomad EAS exome AF: 0.00141

Gnomad FIN exome AF: 0.0612

Gnomad NFE exome AF: 0.0281

Gnomad OTH exome AF: 0.0432

GnomAD4 exome AF: 0.0346 AC: 50462 AN: 1459214 Hom.: 1316 Cov.: 32 AF XY: 0.0342 AC XY: 24863 AN XY: 725982

African (AFR) AF: 0.110 AC: 3674 AN: 33358

American (AMR) AF: 0.108 AC: 4809 AN: 44658

Ashkenazi Jewish (ASJ) AF: 0.0119 AC: 311 AN: 26112

East Asian (EAS) AF: 0.000680 AC: 27 AN: 39690

South Asian (SAS) AF: 0.0447 AC: 3852 AN: 86190

European-Finnish (FIN) AF: 0.0588 AC: 3120 AN: 53092

Middle Eastern (MID) AF: 0.0323 AC: 186 AN: 5754

European-Non Finnish (NFE) AF: 0.0291 AC: 32293 AN: 1110088

Other (OTH) AF: 0.0363 AC: 2190 AN: 60272

GnomAD4 genome AF: 0.0558 AC: 8417 AN: 150792 Hom.: 366 Cov.: 32 AF XY: 0.0572 AC XY: 4202 AN XY: 73524

African (AFR) AF: 0.106 AC: 4344 AN: 40926

American (AMR) AF: 0.0791 AC: 1191 AN: 15052

Ashkenazi Jewish (ASJ) AF: 0.0121 AC: 42 AN: 3470

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5164

South Asian (SAS) AF: 0.0433 AC: 204 AN: 4708

European-Finnish (FIN) AF: 0.0566 AC: 583 AN: 10296

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

European-Non Finnish (NFE) AF: 0.0286 AC: 1942 AN: 67872

Other (OTH) AF: 0.0500 AC: 105 AN: 2098

Alfa AF: 0.0377 Hom.: 414

Bravo AF: 0.0604

TwinsUK AF: 0.0313 AC: 116

ALSPAC AF: 0.0262 AC: 101

ESP6500AA AF: 0.107 AC: 473

ESP6500EA AF: 0.0327 AC: 281

ExAC AF: 0.0443 AC: 5372

Asia WGS AF: 0.0320 AC: 111 AN: 3478

EpiCase AF: 0.0256

EpiControl AF: 0.0279

ClinVar

ClinVar submissions

Significance: 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	0.061
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	11
DANN	Benign	0.95
DEOGEN2	Benign	0.080	T
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.49	T
MetaRNN	Benign	0.0021	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-1.1	N
PhyloP100		4.4
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.97	N
REVEL	Benign	0.060
Sift	Benign	0.56	T
Sift4G	Benign	0.26	T
Polyphen		0.0	B
Vest4		0.21
MPC		0.041
ClinPred		0.0069	T
GERP RS		3.7
Varity_R		0.032
gMVP		0.17
Mutation Taster		=99/1	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: rs34627722; hg19: chr9-399255; COSMIC: COSV66618859;