9-451977-ATTTTTTTTTTTTTTTTT-ATTT

Variant names:

• chr9-451977-ATTTTTTTTTTTTTT-A
• rs35071801
• NM_203447.4:c.5962-22_5962-9delTTTTTTTTTTTTTT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_203447.4(DOCK8):​c.5962-22_5962-9delTTTTTTTTTTTTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.0063 (3 hom., cov: 0)
  • Exomes 𝑓: 0.0051 (21 hom.)
  • Failed GnomAD Quality Control
• Consequence: DOCK8 NM_203447.4 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.34
• Publications: 1 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: Benign. The variant received -16 ACMG points.

• BP6: Variant 9-451977-ATTTTTTTTTTTTTT-A is Benign according to our data. Variant chr9-451977-ATTTTTTTTTTTTTT-A is described in ClinVar as [Likely_benign]. Clinvar id is 1137971.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00627 (521/83054) while in subpopulation AFR AF = 0.0238 (416/17494). AF 95% confidence interval is 0.0219. There are 3 homozygotes in GnomAd4. There are 246 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DOCK8	NM_203447.4	c.5962-22_5962-9delTTTTTTTTTTTTTT		intron_variant	Intron 45 of 47	ENST00000432829.7	NP_982272.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DOCK8	ENST00000432829.7	c.5962-33_5962-20delTTTTTTTTTTTTTT		intron_variant	Intron 45 of 47	1	NM_203447.4	ENSP00000394888.3

Frequencies

GnomAD3 genomes AF: 0.00627 AC: 521 AN: 83070 Hom.: 3 Cov.: 0

Gnomad AFR AF: 0.0238

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00408

Gnomad ASJ AF: 0.000789

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00227

Gnomad FIN AF: 0.000476

Gnomad MID AF: 0.00758

Gnomad NFE AF: 0.00133

Gnomad OTH AF: 0.00398

GnomAD2 exomes AF: 0.00586 AC: 179 AN: 30526 AF XY: 0.00528

Gnomad AFR exome AF: 0.0283

Gnomad AMR exome AF: 0.00264

Gnomad ASJ exome AF: 0.00317

Gnomad EAS exome AF: 0.000427

Gnomad FIN exome AF: 0.00855

Gnomad NFE exome AF: 0.00539

Gnomad OTH exome AF: 0.00822

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00515 AC: 521 AN: 101258 Hom.: 21 AF XY: 0.00494 AC XY: 301 AN XY: 60912

African (AFR) AF: 0.0407 AC: 60 AN: 1474

American (AMR) AF: 0.00455 AC: 19 AN: 4180

Ashkenazi Jewish (ASJ) AF: 0.00517 AC: 14 AN: 2706

East Asian (EAS) AF: 0.000397 AC: 2 AN: 5034

South Asian (SAS) AF: 0.0137 AC: 116 AN: 8480

European-Finnish (FIN) AF: 0.00567 AC: 23 AN: 4056

Middle Eastern (MID) AF: 0.0169 AC: 6 AN: 354

European-Non Finnish (NFE) AF: 0.00356 AC: 249 AN: 70016

Other (OTH) AF: 0.00645 AC: 32 AN: 4958

GnomAD4 genome AF: 0.00627 AC: 521 AN: 83054 Hom.: 3 Cov.: 0 AF XY: 0.00654 AC XY: 246 AN XY: 37616

African (AFR) AF: 0.0238 AC: 416 AN: 17494

American (AMR) AF: 0.00408 AC: 30 AN: 7356

Ashkenazi Jewish (ASJ) AF: 0.000789 AC: 2 AN: 2534

East Asian (EAS) AF: 0.00 AC: 0 AN: 3506

South Asian (SAS) AF: 0.00229 AC: 6 AN: 2624

European-Finnish (FIN) AF: 0.000476 AC: 1 AN: 2100

Middle Eastern (MID) AF: 0.00794 AC: 1 AN: 126

European-Non Finnish (NFE) AF: 0.00133 AC: 61 AN: 45694

Other (OTH) AF: 0.00395 AC: 4 AN: 1012

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Sep 28, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Benign:1

Jan 24, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.3
La Branchor		0.26
BranchPoint Hunter		4.0
Mutation Taster		=100/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs35071801; hg19: chr9-451977;