chr9-451977-ATTTTTTTTTTTT-A

Variant names:

• chr9-451977-ATTTTTTTTTTTT-A
• rs35071801
• NM_203447.4:c.5962-20_5962-9delTTTTTTTTTTTT

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP6_Very_Strong BS1

The NM_203447.4(DOCK8):​c.5962-20_5962-9delTTTTTTTTTTTT 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 0.0036 (0 hom., cov: 0)
  • Exomes 𝑓: 0.018 (65 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 -12 ACMG points.

• BP6: Variant 9-451977-ATTTTTTTTTTTT-A is Benign according to our data. Variant chr9-451977-ATTTTTTTTTTTT-A is described in ClinVar as [Likely_benign]. Clinvar id is 1187429.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 = 0.0036 (299/83044) while in subpopulation AFR AF = 0.00766 (134/17492). AF 95% confidence interval is 0.00661. There are 0 homozygotes in GnomAd4. There are 129 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DOCK8	NM_203447.4	c.5962-20_5962-9delTTTTTTTTTTTT		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_5962-22delTTTTTTTTTTTT		intron_variant	Intron 45 of 47	1	NM_203447.4	ENSP00000394888.3

Frequencies

GnomAD3 genomes AF: 0.00360 AC: 299 AN: 83060 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00761

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00204

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00151

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00317

Gnomad OTH AF: 0.00199

GnomAD2 exomes AF: 0.00884 AC: 270 AN: 30526 AF XY: 0.00867

Gnomad AFR exome AF: 0.0293

Gnomad AMR exome AF: 0.00725

Gnomad ASJ exome AF: 0.00635

Gnomad EAS exome AF: 0.000427

Gnomad FIN exome AF: 0.00741

Gnomad NFE exome AF: 0.0109

Gnomad OTH exome AF: 0.00959

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0179 AC: 1798 AN: 100726 Hom.: 65 AF XY: 0.0169 AC XY: 1024 AN XY: 60570

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0231 AC: 34 AN: 1474

American (AMR) AF: 0.00886 AC: 37 AN: 4174

Ashkenazi Jewish (ASJ) AF: 0.0135 AC: 36 AN: 2676

East Asian (EAS) AF: 0.00358 AC: 18 AN: 5030

South Asian (SAS) AF: 0.0136 AC: 115 AN: 8448

European-Finnish (FIN) AF: 0.0226 AC: 91 AN: 4030

Middle Eastern (MID) AF: 0.0198 AC: 7 AN: 354

European-Non Finnish (NFE) AF: 0.0197 AC: 1372 AN: 69580

Other (OTH) AF: 0.0177 AC: 88 AN: 4960

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00360 AC: 299 AN: 83044 Hom.: 0 Cov.: 0 AF XY: 0.00343 AC XY: 129 AN XY: 37614

African (AFR) AF: 0.00766 AC: 134 AN: 17492

American (AMR) AF: 0.00204 AC: 15 AN: 7356

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2532

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

South Asian (SAS) AF: 0.00152 AC: 4 AN: 2624

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2100

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 126

European-Non Finnish (NFE) AF: 0.00315 AC: 144 AN: 45688

Other (OTH) AF: 0.00198 AC: 2 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 02, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Benign:1

Nov 22, 2024

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;