rs140403518

Variant names:

• chr9-446401-A-G
• rs140403518
• NM_203447.4:c.5612A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_203447.4(DOCK8):​c.5612A>G​(p.Tyr1871Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000471 in 1,614,052 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00045 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00047 (0 hom.)
• Consequence: DOCK8 NM_203447.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:7 O:1
• Conservation: PhyloP100: 3.45
• Publications: 2 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.24071813).

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.5612A>G	p.Tyr1871Cys	missense	Exon 44 of 48	NP_982272.2	Q8NF50-1
	DOCK8	NM_001193536.2		c.5408A>G	p.Tyr1803Cys	missense	Exon 43 of 47	NP_001180465.1	Q8NF50-3
	DOCK8	NM_001190458.2		c.5312A>G	p.Tyr1771Cys	missense	Exon 42 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.5612A>G	p.Tyr1871Cys	missense	Exon 44 of 48	ENSP00000394888.3	Q8NF50-1
	DOCK8	ENST00000469391.5	TSL:1	c.5312A>G	p.Tyr1771Cys	missense	Exon 42 of 46	ENSP00000419438.1	Q8NF50-4
	DOCK8	ENST00000382329.2	TSL:1	c.5312A>G	p.Tyr1771Cys	missense	Exon 43 of 46	ENSP00000371766.2	A2A369

Frequencies

GnomAD3 genomes AF: 0.000453 AC: 69 AN: 152170 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000764

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000410 AC: 103 AN: 251454 AF XY: 0.000412

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.000462

Gnomad NFE exome AF: 0.000783

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000473 AC: 691 AN: 1461882 Hom.: 0 Cov.: 32 AF XY: 0.000458 AC XY: 333 AN XY: 727242

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.0000447 AC: 2 AN: 44724

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

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86256

European-Finnish (FIN) AF: 0.000412 AC: 22 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000588 AC: 654 AN: 1112006

Other (OTH) AF: 0.000166 AC: 10 AN: 60396

GnomAD4 genome AF: 0.000453 AC: 69 AN: 152170 Hom.: 0 Cov.: 33 AF XY: 0.000363 AC XY: 27 AN XY: 74332

African (AFR) AF: 0.0000965 AC: 4 AN: 41434

American (AMR) AF: 0.0000654 AC: 1 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000764 AC: 52 AN: 68024

Other (OTH) AF: 0.000478 AC: 1 AN: 2092

Alfa AF: 0.000541 Hom.: 0

Bravo AF: 0.000408

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000461 AC: 56

EpiCase AF: 0.000491

EpiControl AF: 0.000533

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	4	-	not provided (4)
-	1	-	Combined immunodeficiency due to DOCK8 deficiency (2)
-	1	-	Hyper-IgE recurrent infection syndrome 3, autosomal recessive (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.090
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.33	T
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Benign	0.69	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.24	T
MetaSVM	Benign	-0.85	T
MutationAssessor	Pathogenic	3.4	M
PhyloP100		3.4
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-7.6	D
REVEL	Uncertain	0.34
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.88
MVP		0.41
MPC		0.32
ClinPred		0.70	D
GERP RS		4.0
Varity_R		0.72
gMVP		0.74
Mutation Taster		=77/23	polymorphism

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: rs140403518; hg19: chr9-446401;