NM_203447.4:c.5154C>G

Variant names:

• chr9-439319-C-G
• rs140431229
• NM_203447.4:c.5154C>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_203447.4(DOCK8):​c.5154C>G​(p.Cys1718Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,876 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. C1718C) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: DOCK8 NM_203447.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.143
• Publications: 0 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: Orphanet, ClinGen, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, Genomics England PanelApp
• 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.898

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DOCK8	NM_203447.4	MANE Select	c.5154C>G	p.Cys1718Trp	missense	Exon 40 of 48	NP_982272.2
	DOCK8	NM_001193536.2		c.4950C>G	p.Cys1650Trp	missense	Exon 39 of 47	NP_001180465.1
	DOCK8	NM_001190458.2		c.4854C>G	p.Cys1618Trp	missense	Exon 38 of 46	NP_001177387.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DOCK8	ENST00000432829.7	TSL:1 MANE Select	c.5154C>G	p.Cys1718Trp	missense	Exon 40 of 48	ENSP00000394888.3
	DOCK8	ENST00000469391.5	TSL:1	c.4854C>G	p.Cys1618Trp	missense	Exon 38 of 46	ENSP00000419438.1
	DOCK8	ENST00000382329.2	TSL:1	c.4854C>G	p.Cys1618Trp	missense	Exon 39 of 46	ENSP00000371766.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461876 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727244

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 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: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

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

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1112008

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.39	T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.44
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Benign	-0.90	T
MutationAssessor	Pathogenic	3.2	M
PhyloP100		-0.14
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-10	D
REVEL	Uncertain	0.42
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.91
MutPred		0.54		Loss of catalytic residue at C1718 (P = 0.0909)
MVP		0.28
MPC		0.34
ClinPred		1.0	D
GERP RS		-0.0068
Varity_R		0.91
gMVP		0.85
Mutation Taster		=46/54	disease causing

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: rs140431229; hg19: chr9-439319;