9-441952-G-T

Variant names:

• chr9-441952-G-T
• rs1887957
• NM_203447.4:c.5433G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_203447.4(DOCK8):​c.5433G>T​(p.Glu1811Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E1811Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: DOCK8 NM_203447.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.269
• Publications: 26 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.5433G>T	p.Glu1811Asp	missense	Exon 42 of 48	NP_982272.2
	DOCK8	NM_001193536.2		c.5229G>T	p.Glu1743Asp	missense	Exon 41 of 47	NP_001180465.1
	DOCK8	NM_001190458.2		c.5133G>T	p.Glu1711Asp	missense	Exon 40 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.5433G>T	p.Glu1811Asp	missense	Exon 42 of 48	ENSP00000394888.3
	DOCK8	ENST00000469391.5	TSL:1	c.5133G>T	p.Glu1711Asp	missense	Exon 40 of 46	ENSP00000419438.1
	DOCK8	ENST00000382329.2	TSL:1	c.5133G>T	p.Glu1711Asp	missense	Exon 41 of 46	ENSP00000371766.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 55

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.71
BayesDel_addAF	Benign	-0.032	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.32	T
Eigen	Uncertain	0.19
Eigen_PC	Benign	0.067
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.016	T
MetaRNN	Uncertain	0.45	T
MetaSVM	Benign	-0.68	T
MutationAssessor	Pathogenic	3.2	M
PhyloP100		0.27
PrimateAI	Pathogenic	0.79	T
PROVEAN	Uncertain	-2.7	D
REVEL	Uncertain	0.30
Sift	Uncertain	0.0030	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.99	D
Vest4		0.47
MutPred		0.42		Loss of catalytic residue at E1811 (P = 0.0537)
MVP		0.36
MPC		0.12
ClinPred		0.96	D
GERP RS		1.7
Varity_R		0.53
gMVP		0.73
Mutation Taster		=74/26	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: rs1887957; hg19: chr9-441952;