9-451977-ATTTTTTTTTTTTTTTTT-AT

Variant names:

• chr9-451977-ATTTTTTTTTTTTTTTT-A
• rs35071801
• NM_203447.4:c.5962-24_5962-9delTTTTTTTTTTTTTTTT

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_203447.4(DOCK8):​c.5962-24_5962-9delTTTTTTTTTTTTTTTT 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 0.0057 (3 hom., cov: 0)
  • Exomes 𝑓: 0.0068 (13 hom.)
  • Failed GnomAD Quality Control
• Consequence: DOCK8 NM_203447.4 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• 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 -10 ACMG points.

• BP6: Variant 9-451977-ATTTTTTTTTTTTTTTT-A is Benign according to our data. Variant chr9-451977-ATTTTTTTTTTTTTTTT-A is described in ClinVar as [Likely_benign]. Clinvar id is 1143987.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00567 (471/83056) while in subpopulation NFE AF = 0.00742 (339/45694). AF 95% confidence interval is 0.00677. There are 3 homozygotes in GnomAd4. There are 228 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.5962-24_5962-9delTTTTTTTTTTTTTTTT		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_5962-18delTTTTTTTTTTTTTTTT		intron_variant	Intron 45 of 47	1	NM_203447.4	ENSP00000394888.3

Frequencies

GnomAD3 genomes AF: 0.00567 AC: 471 AN: 83072 Hom.: 3 Cov.: 0

Gnomad AFR AF: 0.00229

Gnomad AMI AF: 0.0164

Gnomad AMR AF: 0.00394

Gnomad ASJ AF: 0.00276

Gnomad EAS AF: 0.00114

Gnomad SAS AF: 0.00680

Gnomad FIN AF: 0.00476

Gnomad MID AF: 0.0227

Gnomad NFE AF: 0.00742

Gnomad OTH AF: 0.0110

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00678 AC: 688 AN: 101414 Hom.: 13 AF XY: 0.00638 AC XY: 389 AN XY: 61002

African (AFR) AF: 0.000672 AC: 1 AN: 1488

American (AMR) AF: 0.00406 AC: 17 AN: 4186

Ashkenazi Jewish (ASJ) AF: 0.00443 AC: 12 AN: 2706

East Asian (EAS) AF: 0.000397 AC: 2 AN: 5036

South Asian (SAS) AF: 0.00436 AC: 37 AN: 8486

European-Finnish (FIN) AF: 0.00786 AC: 32 AN: 4072

Middle Eastern (MID) AF: 0.0225 AC: 8 AN: 356

European-Non Finnish (NFE) AF: 0.00765 AC: 536 AN: 70108

Other (OTH) AF: 0.00864 AC: 43 AN: 4976

GnomAD4 genome AF: 0.00567 AC: 471 AN: 83056 Hom.: 3 Cov.: 0 AF XY: 0.00606 AC XY: 228 AN XY: 37620

African (AFR) AF: 0.00229 AC: 40 AN: 17494

American (AMR) AF: 0.00394 AC: 29 AN: 7358

Ashkenazi Jewish (ASJ) AF: 0.00276 AC: 7 AN: 2534

East Asian (EAS) AF: 0.00114 AC: 4 AN: 3506

South Asian (SAS) AF: 0.00686 AC: 18 AN: 2624

European-Finnish (FIN) AF: 0.00476 AC: 10 AN: 2100

Middle Eastern (MID) AF: 0.0238 AC: 3 AN: 126

European-Non Finnish (NFE) AF: 0.00742 AC: 339 AN: 45694

Other (OTH) AF: 0.0109 AC: 11 AN: 1012

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Benign:1

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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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;