rs112565335

chr9-399266-GT-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_203447.4(DOCK8):c.3234+8del variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0116 in 1,593,902 control chromosomes in the GnomAD database, including 1,806 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.065 (908 hom., cov: 30)
  • Exomes 𝑓: 0.0066 (898 hom.)
• Consequence: DOCK8 NM_203447.4 splice_region, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.137

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP6: Variant 9-399266-GT-G is Benign according to our data. Variant chr9-399266-GT-G is described in ClinVar as [Benign]. Clinvar id is 402793.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.227 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DOCK8	NM_203447.4	c.3234+8del		splice_region_variant, intron_variant		ENST00000432829.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DOCK8	ENST00000432829.7	c.3234+8del		splice_region_variant, intron_variant		1	NM_203447.4

Frequencies

GnomAD3 genomes AF: 0.0647 AC: 8973 AN: 138702 Hom.: 908 Cov.: 30

Gnomad AFR AF: 0.232

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0234

Gnomad ASJ AF: 0.00208

Gnomad EAS AF: 0.000206

Gnomad SAS AF: 0.000554

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00704

Gnomad NFE AF: 0.000723

Gnomad OTH AF: 0.0431

GnomAD3 exomes AF: 0.0164 AC: 4029 AN: 245400 Hom.: 407 AF XY: 0.0118 AC XY: 1577 AN XY: 133138

Gnomad AFR exome AF: 0.232

Gnomad AMR exome AF: 0.0109

Gnomad ASJ exome AF: 0.00200

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000405

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000440

Gnomad OTH exome AF: 0.00719

GnomAD4 exome AF: 0.00655 AC: 9531 AN: 1455110 Hom.: 898 Cov.: 30 AF XY: 0.00559 AC XY: 4048 AN XY: 724182

Gnomad4 AFR exome AF: 0.233

Gnomad4 AMR exome AF: 0.0126

Gnomad4 ASJ exome AF: 0.00195

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000604

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000227

Gnomad4 OTH exome AF: 0.0141

GnomAD4 genome AF: 0.0647 AC: 8977 AN: 138792 Hom.: 908 Cov.: 30 AF XY: 0.0631 AC XY: 4255 AN XY: 67452

Gnomad4 AFR AF: 0.231

Gnomad4 AMR AF: 0.0233

Gnomad4 ASJ AF: 0.00208

Gnomad4 EAS AF: 0.000207

Gnomad4 SAS AF: 0.000554

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000723

Gnomad4 OTH AF: 0.0429

Alfa AF: 0.00438 Hom.: 7

Asia WGS AF: 0.00906 AC: 31 AN: 3436

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 29, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Apr 29, 2018

- -

Autosomal recessive hyper-IgE syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

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: rs112565335; hg19: chr9-399266;