9-451977-ATTTTTTTTTTTTTTTTT-ATTTTTT

Variant names:

• chr9-451977-ATTTTTTTTTTT-A
• rs35071801
• NM_203447.4:c.5962-19_5962-9delTTTTTTTTTTT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_203447.4(DOCK8):​c.5962-19_5962-9delTTTTTTTTTTT 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 0.11 (563 hom., cov: 0)
  • Exomes 𝑓: 0.14 (1436 hom.)
  • Failed GnomAD Quality Control
• Consequence: DOCK8 NM_203447.4 intron
• Clinical Significance: Benign/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-ATTTTTTTTTTT-A is Benign according to our data. Variant chr9-451977-ATTTTTTTTTTT-A is described in ClinVar as [Likely_benign]. Clinvar id is 1282256.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.142 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DOCK8	NM_203447.4	c.5962-19_5962-9delTTTTTTTTTTT		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_5962-23delTTTTTTTTTTT		intron_variant	Intron 45 of 47	1	NM_203447.4	ENSP00000394888.3

Frequencies

GnomAD3 genomes AF: 0.114 AC: 9423 AN: 82934 Hom.: 562 Cov.: 0

Gnomad AFR AF: 0.0591

Gnomad AMI AF: 0.169

Gnomad AMR AF: 0.0904

Gnomad ASJ AF: 0.0962

Gnomad EAS AF: 0.0298

Gnomad SAS AF: 0.0726

Gnomad FIN AF: 0.154

Gnomad MID AF: 0.0758

Gnomad NFE AF: 0.145

Gnomad OTH AF: 0.121

GnomAD2 exomes AF: 0.0539 AC: 1645 AN: 30526 AF XY: 0.0514

Gnomad AFR exome AF: 0.0446

Gnomad AMR exome AF: 0.0349

Gnomad ASJ exome AF: 0.0468

Gnomad EAS exome AF: 0.0128

Gnomad FIN exome AF: 0.0753

Gnomad NFE exome AF: 0.0773

Gnomad OTH exome AF: 0.0507

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.137 AC: 13506 AN: 98506 Hom.: 1436 AF XY: 0.133 AC XY: 7902 AN XY: 59240

African (AFR) AF: 0.0820 AC: 120 AN: 1464

American (AMR) AF: 0.0952 AC: 387 AN: 4066

Ashkenazi Jewish (ASJ) AF: 0.136 AC: 351 AN: 2580

East Asian (EAS) AF: 0.0361 AC: 180 AN: 4984

South Asian (SAS) AF: 0.0797 AC: 655 AN: 8214

European-Finnish (FIN) AF: 0.142 AC: 559 AN: 3924

Middle Eastern (MID) AF: 0.0862 AC: 30 AN: 348

European-Non Finnish (NFE) AF: 0.156 AC: 10589 AN: 68080

Other (OTH) AF: 0.131 AC: 635 AN: 4846

GnomAD4 genome AF: 0.114 AC: 9418 AN: 82916 Hom.: 563 Cov.: 0 AF XY: 0.110 AC XY: 4124 AN XY: 37556

African (AFR) AF: 0.0590 AC: 1030 AN: 17460

American (AMR) AF: 0.0904 AC: 663 AN: 7336

Ashkenazi Jewish (ASJ) AF: 0.0962 AC: 244 AN: 2536

East Asian (EAS) AF: 0.0294 AC: 103 AN: 3506

South Asian (SAS) AF: 0.0736 AC: 193 AN: 2622

European-Finnish (FIN) AF: 0.154 AC: 321 AN: 2090

Middle Eastern (MID) AF: 0.0714 AC: 9 AN: 126

European-Non Finnish (NFE) AF: 0.145 AC: 6631 AN: 45622

Other (OTH) AF: 0.120 AC: 122 AN: 1014

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Aug 10, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Benign:1

Jan 13, 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 (auto)

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;