NM_203447.4:c.4785+6C>G

Variant names:

• chr9-432330-C-G
• rs7036567
• NM_203447.4:c.4785+6C>G

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.4785+6C>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.757 in 1,613,316 control chromosomes in the GnomAD database, including 466,623 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.70 (38123 hom., cov: 30)
  • Exomes 𝑓: 0.76 (428500 hom.)
• Consequence: DOCK8 NM_203447.4 splice_region, intron
• Scores: Splicing: ADA: 0.00009776
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10 O:1
• Conservation: PhyloP100: 0.213
• Publications: 13 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 (BayesDel_noAF=-0.78).
• BP6: Variant 9-432330-C-G is Benign according to our data. Variant chr9-432330-C-G is described in ClinVar as Benign. ClinVar VariationId is 163176.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.958 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.4785+6C>G		splice_region intron	N/A	NP_982272.2	Q8NF50-1
	DOCK8	NM_001193536.2		c.4581+6C>G		splice_region intron	N/A	NP_001180465.1	Q8NF50-3
	DOCK8	NM_001190458.2		c.4485+6C>G		splice_region intron	N/A	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.4785+6C>G		splice_region intron	N/A	ENSP00000394888.3	Q8NF50-1
	DOCK8	ENST00000469391.5	TSL:1	c.4485+6C>G		splice_region intron	N/A	ENSP00000419438.1	Q8NF50-4
	DOCK8	ENST00000382329.2	TSL:1	c.4485+6C>G		splice_region intron	N/A	ENSP00000371766.2	A2A369

Frequencies

GnomAD3 genomes AF: 0.696 AC: 105596 AN: 151788 Hom.: 38106 Cov.: 30

Gnomad AFR AF: 0.487

Gnomad AMI AF: 0.638

Gnomad AMR AF: 0.793

Gnomad ASJ AF: 0.732

Gnomad EAS AF: 0.981

Gnomad SAS AF: 0.689

Gnomad FIN AF: 0.788

Gnomad MID AF: 0.759

Gnomad NFE AF: 0.763

Gnomad OTH AF: 0.711

GnomAD2 exomes AF: 0.766 AC: 192546 AN: 251346 AF XY: 0.763

Gnomad AFR exome AF: 0.481

Gnomad AMR exome AF: 0.852

Gnomad ASJ exome AF: 0.712

Gnomad EAS exome AF: 0.985

Gnomad FIN exome AF: 0.795

Gnomad NFE exome AF: 0.766

Gnomad OTH exome AF: 0.757

GnomAD4 exome AF: 0.763 AC: 1114842 AN: 1461410 Hom.: 428500 Cov.: 47 AF XY: 0.761 AC XY: 553218 AN XY: 727042

African (AFR) AF: 0.476 AC: 15910 AN: 33454

American (AMR) AF: 0.845 AC: 37799 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.713 AC: 18623 AN: 26124

East Asian (EAS) AF: 0.980 AC: 38920 AN: 39696

South Asian (SAS) AF: 0.689 AC: 59416 AN: 86244

European-Finnish (FIN) AF: 0.794 AC: 42390 AN: 53412

Middle Eastern (MID) AF: 0.701 AC: 4039 AN: 5764

European-Non Finnish (NFE) AF: 0.766 AC: 852028 AN: 1111626

Other (OTH) AF: 0.757 AC: 45717 AN: 60378

GnomAD4 genome AF: 0.696 AC: 105662 AN: 151906 Hom.: 38123 Cov.: 30 AF XY: 0.700 AC XY: 51954 AN XY: 74238

African (AFR) AF: 0.487 AC: 20150 AN: 41360

American (AMR) AF: 0.793 AC: 12106 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.732 AC: 2542 AN: 3472

East Asian (EAS) AF: 0.981 AC: 5068 AN: 5166

South Asian (SAS) AF: 0.690 AC: 3320 AN: 4812

European-Finnish (FIN) AF: 0.788 AC: 8309 AN: 10548

Middle Eastern (MID) AF: 0.759 AC: 223 AN: 294

European-Non Finnish (NFE) AF: 0.763 AC: 51864 AN: 67974

Other (OTH) AF: 0.713 AC: 1502 AN: 2106

Alfa AF: 0.730 Hom.: 10715

Bravo AF: 0.690

Asia WGS AF: 0.823 AC: 2862 AN: 3478

EpiCase AF: 0.751

EpiControl AF: 0.763

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	2	Combined immunodeficiency due to DOCK8 deficiency (2)
-	-	2	not provided (3)
-	-	1	Not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	6.6
DANN	Benign	0.49
PhyloP100		0.21
Mutation Taster		=88/12	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000098
dbscSNV1_RF	Benign	0.042
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: rs7036567; hg19: chr9-432330;