9-451977-ATTTTTTTTTTTTTTTTT-ATTTTTTTT

Variant names:

• chr9-451977-ATTTTTTTTT-A
• rs35071801
• NM_203447.4:c.5962-17_5962-9delTTTTTTTTT

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.5962-17_5962-9delTTTTTTTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.29 (2810 hom., cov: 10)
  • Exomes 𝑓: 0.31 (4223 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-ATTTTTTTTT-A is Benign according to our data. Variant chr9-451977-ATTTTTTTTT-A is described in ClinVar as [Likely_benign]. Clinvar id is 1182262.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.333 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DOCK8	NM_203447.4	c.5962-17_5962-9delTTTTTTTTT		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_5962-25delTTTTTTTTT		intron_variant	Intron 45 of 47	1	NM_203447.4	ENSP00000394888.3

Frequencies

GnomAD3 genomes AF: 0.288 AC: 23432 AN: 81318 Hom.: 2809 Cov.: 10

Gnomad AFR AF: 0.157

Gnomad AMI AF: 0.333

Gnomad AMR AF: 0.272

Gnomad ASJ AF: 0.288

Gnomad EAS AF: 0.328

Gnomad SAS AF: 0.281

Gnomad FIN AF: 0.298

Gnomad MID AF: 0.381

Gnomad NFE AF: 0.338

Gnomad OTH AF: 0.269

GnomAD2 exomes AF: 0.0897 AC: 2738 AN: 30526 AF XY: 0.0886

Gnomad AFR exome AF: 0.0402

Gnomad AMR exome AF: 0.0982

Gnomad ASJ exome AF: 0.0599

Gnomad EAS exome AF: 0.131

Gnomad FIN exome AF: 0.0667

Gnomad NFE exome AF: 0.100

Gnomad OTH exome AF: 0.112

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.308 AC: 27278 AN: 88684 Hom.: 4223 AF XY: 0.311 AC XY: 16438 AN XY: 52874

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

African (AFR) AF: 0.195 AC: 264 AN: 1352

American (AMR) AF: 0.292 AC: 1029 AN: 3524

Ashkenazi Jewish (ASJ) AF: 0.274 AC: 637 AN: 2326

East Asian (EAS) AF: 0.342 AC: 1465 AN: 4286

South Asian (SAS) AF: 0.281 AC: 1950 AN: 6940

European-Finnish (FIN) AF: 0.288 AC: 1042 AN: 3618

Middle Eastern (MID) AF: 0.299 AC: 92 AN: 308

European-Non Finnish (NFE) AF: 0.314 AC: 19444 AN: 61914

Other (OTH) AF: 0.307 AC: 1355 AN: 4416

⚠️ 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: 0.288 AC: 23414 AN: 81298 Hom.: 2810 Cov.: 10 AF XY: 0.284 AC XY: 10490 AN XY: 36872

African (AFR) AF: 0.157 AC: 2721 AN: 17306

American (AMR) AF: 0.272 AC: 1963 AN: 7224

Ashkenazi Jewish (ASJ) AF: 0.288 AC: 710 AN: 2468

East Asian (EAS) AF: 0.329 AC: 1129 AN: 3434

South Asian (SAS) AF: 0.281 AC: 719 AN: 2558

European-Finnish (FIN) AF: 0.298 AC: 615 AN: 2062

Middle Eastern (MID) AF: 0.367 AC: 44 AN: 120

European-Non Finnish (NFE) AF: 0.338 AC: 15048 AN: 44540

Other (OTH) AF: 0.269 AC: 266 AN: 988

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 13, 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;