rs140270895

Variant names:

• chr9-289520-G-C
• rs140270895
• NM_203447.4:c.343G>C

Your query was ambiguous. Multiple possible variants found:

• chr9-289520-G-C
• chr9-289520-G-A
• chr9-289520-G-T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Moderate BP6_Moderate BS1

The NM_203447.4(DOCK8):​c.343G>C​(p.Asp115His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000998 in 1,613,442 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 Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. D115D) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00063 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000044 (0 hom.)
• Consequence: DOCK8 NM_203447.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 8.63
• 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: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.10184592).
• BP6: Variant 9-289520-G-C is Benign according to our data. Variant chr9-289520-G-C is described in ClinVar as Likely_benign. ClinVar VariationId is 468738.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00063 (96/152276) while in subpopulation AFR AF = 0.00229 (95/41538). AF 95% confidence interval is 0.00191. There are 0 homozygotes in GnomAd4. There are 48 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

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.343G>C	p.Asp115His	missense	Exon 4 of 48	NP_982272.2	Q8NF50-1
	DOCK8	NM_001193536.2		c.139G>C	p.Asp47His	missense	Exon 3 of 47	NP_001180465.1	Q8NF50-3
	DOCK8	NM_001190458.2		c.139G>C	p.Asp47His	missense	Exon 3 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.343G>C	p.Asp115His	missense	Exon 4 of 48	ENSP00000394888.3	Q8NF50-1
	DOCK8	ENST00000469391.5	TSL:1	c.139G>C	p.Asp47His	missense	Exon 3 of 46	ENSP00000419438.1	Q8NF50-4
	DOCK8	ENST00000382329.2	TSL:1	c.139G>C	p.Asp47His	missense	Exon 4 of 46	ENSP00000371766.2	A2A369

Frequencies

GnomAD3 genomes AF: 0.000631 AC: 96 AN: 152158 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00229

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000127 AC: 32 AN: 251278 AF XY: 0.0000957

Gnomad AFR exome AF: 0.00185

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000445 AC: 65 AN: 1461166 Hom.: 0 Cov.: 31 AF XY: 0.0000426 AC XY: 31 AN XY: 726908

African (AFR) AF: 0.00185 AC: 62 AN: 33436

American (AMR) AF: 0.0000447 AC: 2 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39668

South Asian (SAS) AF: 0.00 AC: 0 AN: 86230

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53360

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111554

Other (OTH) AF: 0.0000166 AC: 1 AN: 60344

GnomAD4 genome AF: 0.000630 AC: 96 AN: 152276 Hom.: 0 Cov.: 33 AF XY: 0.000645 AC XY: 48 AN XY: 74468

African (AFR) AF: 0.00229 AC: 95 AN: 41538

American (AMR) AF: 0.0000654 AC: 1 AN: 15302

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000427 Hom.: 0

Bravo AF: 0.000525

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000132 AC: 16

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Benign	-0.0099	T
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.35	T
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-0.64	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		8.6
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-6.5	D
REVEL	Uncertain	0.53
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.028	D
Polyphen		1.0	D
Vest4		0.83
MVP		0.69
MPC		0.32
ClinPred		0.29	T
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.82
gMVP		0.56
Mutation Taster		=60/40	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: rs140270895; hg19: chr9-289520;