chr9-451977-ATTTTTTTT-A

Variant names:

• chr9-451977-ATTTTTTTT-A
• rs35071801
• NM_203447.4:c.5962-16_5962-9delTTTTTTTT

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.5962-16_5962-9delTTTTTTTT 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 0.016 (12 hom., cov: 10)
  • Exomes 𝑓: 0.016 (172 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-ATTTTTTTT-A is Benign according to our data. Variant chr9-451977-ATTTTTTTT-A is described in ClinVar as [Likely_benign]. Clinvar id is 1194486.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0161 (1334/82950) while in subpopulation EAS AF = 0.0447 (156/3490). AF 95% confidence interval is 0.039. There are 12 homozygotes in GnomAd4. There are 626 alleles in the male GnomAd4 subpopulation. Median coverage is 10. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 12 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DOCK8	NM_203447.4	c.5962-16_5962-9delTTTTTTTT		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_5962-26delTTTTTTTT		intron_variant	Intron 45 of 47	1	NM_203447.4	ENSP00000394888.3

Frequencies

GnomAD3 genomes AF: 0.0161 AC: 1334 AN: 82968 Hom.: 12 Cov.: 10

Gnomad AFR AF: 0.0147

Gnomad AMI AF: 0.0313

Gnomad AMR AF: 0.0229

Gnomad ASJ AF: 0.0103

Gnomad EAS AF: 0.0451

Gnomad SAS AF: 0.00983

Gnomad FIN AF: 0.0133

Gnomad MID AF: 0.00758

Gnomad NFE AF: 0.0140

Gnomad OTH AF: 0.0140

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0158 AC: 1574 AN: 99640 Hom.: 172 AF XY: 0.0153 AC XY: 919 AN XY: 59948

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

African (AFR) AF: 0.0306 AC: 45 AN: 1472

American (AMR) AF: 0.0280 AC: 113 AN: 4038

Ashkenazi Jewish (ASJ) AF: 0.00865 AC: 23 AN: 2660

East Asian (EAS) AF: 0.0410 AC: 198 AN: 4824

South Asian (SAS) AF: 0.0146 AC: 121 AN: 8266

European-Finnish (FIN) AF: 0.0173 AC: 69 AN: 3988

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

European-Non Finnish (NFE) AF: 0.0132 AC: 915 AN: 69138

Other (OTH) AF: 0.0171 AC: 84 AN: 4900

⚠️ 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: 0.0161 AC: 1334 AN: 82950 Hom.: 12 Cov.: 10 AF XY: 0.0167 AC XY: 626 AN XY: 37574

African (AFR) AF: 0.0149 AC: 260 AN: 17482

American (AMR) AF: 0.0227 AC: 167 AN: 7350

Ashkenazi Jewish (ASJ) AF: 0.0103 AC: 26 AN: 2532

East Asian (EAS) AF: 0.0447 AC: 156 AN: 3490

South Asian (SAS) AF: 0.00991 AC: 26 AN: 2624

European-Finnish (FIN) AF: 0.0133 AC: 28 AN: 2098

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

European-Non Finnish (NFE) AF: 0.0140 AC: 637 AN: 45630

Other (OTH) AF: 0.0139 AC: 14 AN: 1010

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 06, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Benign:1

Nov 28, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: 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;