9-214908-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_203447.4(DOCK8):c.-69T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0983 in 1,603,930 control chromosomes in the GnomAD database, including 8,213 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.097 (751 hom., cov: 34)
  • Exomes 𝑓: 0.098 (7462 hom.)
• Consequence: DOCK8 NM_203447.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.571

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-AS1 (HGNC:26436): (DOCK8 antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 9-214908-T-C is Benign according to our data. Variant chr9-214908-T-C is described in ClinVar as [Benign]. Clinvar id is 366225.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.111 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DOCK8	NM_203447.4	c.-69T>C		5_prime_UTR_variant	1/48	ENST00000432829.7
DOCK8-AS1	NR_160804.1	n.843A>G		non_coding_transcript_exon_variant	1/1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DOCK8	ENST00000432829.7	c.-69T>C		5_prime_UTR_variant	1/48	1	NM_203447.4
DOCK8-AS1	ENST00000648587.1	n.834A>G		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes AF: 0.0972 AC: 14781 AN: 152006 Hom.: 754 Cov.: 34

Gnomad AFR AF: 0.110

Gnomad AMI AF: 0.177

Gnomad AMR AF: 0.0752

Gnomad ASJ AF: 0.104

Gnomad EAS AF: 0.00309

Gnomad SAS AF: 0.119

Gnomad FIN AF: 0.0933

Gnomad MID AF: 0.0669

Gnomad NFE AF: 0.0998

Gnomad OTH AF: 0.0899

GnomAD3 exomes AF: 0.0905 AC: 20582 AN: 227434 Hom.: 1090 AF XY: 0.0928 AC XY: 11691 AN XY: 126016

Gnomad AFR exome AF: 0.107

Gnomad AMR exome AF: 0.0670

Gnomad ASJ exome AF: 0.103

Gnomad EAS exome AF: 0.00162

Gnomad SAS exome AF: 0.119

Gnomad FIN exome AF: 0.0897

Gnomad NFE exome AF: 0.102

Gnomad OTH exome AF: 0.0891

GnomAD4 exome AF: 0.0984 AC: 142922 AN: 1451816 Hom.: 7462 Cov.: 111 AF XY: 0.0990 AC XY: 71510 AN XY: 722222

Gnomad4 AFR exome AF: 0.115

Gnomad4 AMR exome AF: 0.0669

Gnomad4 ASJ exome AF: 0.103

Gnomad4 EAS exome AF: 0.00193

Gnomad4 SAS exome AF: 0.118

Gnomad4 FIN exome AF: 0.0868

Gnomad4 NFE exome AF: 0.102

Gnomad4 OTH exome AF: 0.0936

GnomAD4 genome AF: 0.0972 AC: 14791 AN: 152114 Hom.: 751 Cov.: 34 AF XY: 0.0953 AC XY: 7089 AN XY: 74378

Gnomad4 AFR AF: 0.110

Gnomad4 AMR AF: 0.0753

Gnomad4 ASJ AF: 0.104

Gnomad4 EAS AF: 0.00310

Gnomad4 SAS AF: 0.119

Gnomad4 FIN AF: 0.0933

Gnomad4 NFE AF: 0.0998

Gnomad4 OTH AF: 0.0889

Alfa AF: 0.101 Hom.: 353

Bravo AF: 0.0952

Asia WGS AF: 0.0560 AC: 194 AN: 3472

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Combined immunodeficiency due to DOCK8 deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 19, 2018

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
Cadd	Benign	11
Dann	Benign	0.65

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

Publications

LitVar

Other links and lift over

dbSNP: rs62533313; hg19: chr9-214908; COSMIC: COSV66688142; COSMIC: COSV66688142;