NM_203447.4:c.5962-18_5962-9delTTTTTTTTTT

Variant names:

• chr9-451977-ATTTTTTTTTT-A
• rs35071801
• NM_203447.4:c.5962-18_5962-9delTTTTTTTTTT

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.5962-18_5962-9delTTTTTTTTTT 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 0.019 (15 hom., cov: 0)
  • Exomes 𝑓: 0.049 (448 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 -16 ACMG points.

• BP6: Variant 9-451977-ATTTTTTTTTT-A is Benign according to our data. Variant chr9-451977-ATTTTTTTTTT-A is described in ClinVar as [Likely_benign]. Clinvar id is 1186822.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 = 0.0186 (1542/83032) while in subpopulation EAS AF = 0.0397 (139/3504). AF 95% confidence interval is 0.0343. There are 15 homozygotes in GnomAd4. There are 713 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 15 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DOCK8	NM_203447.4	c.5962-18_5962-9delTTTTTTTTTT		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_5962-24delTTTTTTTTTT		intron_variant	Intron 45 of 47	1	NM_203447.4	ENSP00000394888.3

Frequencies

GnomAD3 genomes AF: 0.0186 AC: 1545 AN: 83050 Hom.: 15 Cov.: 0

Gnomad AFR AF: 0.0358

Gnomad AMI AF: 0.00164

Gnomad AMR AF: 0.0132

Gnomad ASJ AF: 0.00276

Gnomad EAS AF: 0.0398

Gnomad SAS AF: 0.0170

Gnomad FIN AF: 0.00238

Gnomad MID AF: 0.0303

Gnomad NFE AF: 0.0132

Gnomad OTH AF: 0.0179

GnomAD2 exomes AF: 0.0154 AC: 471 AN: 30526 AF XY: 0.0143

Gnomad AFR exome AF: 0.0228

Gnomad AMR exome AF: 0.0119

Gnomad ASJ exome AF: 0.00595

Gnomad EAS exome AF: 0.0235

Gnomad FIN exome AF: 0.00855

Gnomad NFE exome AF: 0.0171

Gnomad OTH exome AF: 0.0164

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0492 AC: 4849 AN: 98460 Hom.: 448 AF XY: 0.0483 AC XY: 2861 AN XY: 59204

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

African (AFR) AF: 0.0971 AC: 140 AN: 1442

American (AMR) AF: 0.0374 AC: 153 AN: 4094

Ashkenazi Jewish (ASJ) AF: 0.0363 AC: 95 AN: 2618

East Asian (EAS) AF: 0.0678 AC: 330 AN: 4866

South Asian (SAS) AF: 0.0449 AC: 370 AN: 8238

European-Finnish (FIN) AF: 0.0457 AC: 181 AN: 3960

Middle Eastern (MID) AF: 0.0636 AC: 22 AN: 346

European-Non Finnish (NFE) AF: 0.0483 AC: 3286 AN: 68044

Other (OTH) AF: 0.0561 AC: 272 AN: 4852

⚠️ 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: 0.0186 AC: 1542 AN: 83032 Hom.: 15 Cov.: 0 AF XY: 0.0190 AC XY: 713 AN XY: 37618

African (AFR) AF: 0.0358 AC: 625 AN: 17470

American (AMR) AF: 0.0132 AC: 97 AN: 7362

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

East Asian (EAS) AF: 0.0397 AC: 139 AN: 3504

South Asian (SAS) AF: 0.0172 AC: 45 AN: 2622

European-Finnish (FIN) AF: 0.00238 AC: 5 AN: 2100

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

European-Non Finnish (NFE) AF: 0.0132 AC: 602 AN: 45694

Other (OTH) AF: 0.0178 AC: 18 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

Jun 28, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Benign:1

May 06, 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;