9-451977-ATTTTTTTTTTTTTTTTT-ATTTTTTTTTT

Variant names:

• chr9-451977-ATTTTTTT-A
• rs35071801
• NM_203447.4:c.5962-15_5962-9delTTTTTTT

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_203447.4(DOCK8):​c.5962-15_5962-9delTTTTTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.0055 (2 hom., cov: 10)
  • Exomes 𝑓: 0.0035 (18 hom.)
  • Failed GnomAD Quality Control
• Consequence: DOCK8 NM_203447.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• 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 -10 ACMG points.

• BP6: Variant 9-451977-ATTTTTTT-A is Benign according to our data. Variant chr9-451977-ATTTTTTT-A is described in ClinVar as [Benign]. Clinvar id is 1577334.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00548 (455/82972) while in subpopulation AMR AF = 0.0257 (189/7346). AF 95% confidence interval is 0.0227. There are 2 homozygotes in GnomAd4. There are 228 alleles in the male GnomAd4 subpopulation. Median coverage is 10. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DOCK8	NM_203447.4	c.5962-15_5962-9delTTTTTTT		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_5962-27delTTTTTTT		intron_variant	Intron 45 of 47	1	NM_203447.4	ENSP00000394888.3

Frequencies

GnomAD3 genomes AF: 0.00549 AC: 456 AN: 82988 Hom.: 2 Cov.: 10

Gnomad AFR AF: 0.00562

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0257

Gnomad ASJ AF: 0.000395

Gnomad EAS AF: 0.0185

Gnomad SAS AF: 0.00530

Gnomad FIN AF: 0.000955

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00171

Gnomad OTH AF: 0.00898

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00346 AC: 349 AN: 100934 Hom.: 18 AF XY: 0.00331 AC XY: 201 AN XY: 60692

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

African (AFR) AF: 0.00269 AC: 4 AN: 1486

American (AMR) AF: 0.0162 AC: 66 AN: 4078

Ashkenazi Jewish (ASJ) AF: 0.00260 AC: 7 AN: 2692

East Asian (EAS) AF: 0.0140 AC: 69 AN: 4930

South Asian (SAS) AF: 0.00285 AC: 24 AN: 8420

European-Finnish (FIN) AF: 0.00419 AC: 17 AN: 4054

Middle Eastern (MID) AF: 0.00282 AC: 1 AN: 354

European-Non Finnish (NFE) AF: 0.00189 AC: 132 AN: 69962

Other (OTH) AF: 0.00585 AC: 29 AN: 4958

⚠️ 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: 0.00548 AC: 455 AN: 82972 Hom.: 2 Cov.: 10 AF XY: 0.00606 AC XY: 228 AN XY: 37596

African (AFR) AF: 0.00555 AC: 97 AN: 17464

American (AMR) AF: 0.0257 AC: 189 AN: 7346

Ashkenazi Jewish (ASJ) AF: 0.000395 AC: 1 AN: 2534

East Asian (EAS) AF: 0.0186 AC: 65 AN: 3492

South Asian (SAS) AF: 0.00534 AC: 14 AN: 2622

European-Finnish (FIN) AF: 0.000955 AC: 2 AN: 2094

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

European-Non Finnish (NFE) AF: 0.00171 AC: 78 AN: 45676

Other (OTH) AF: 0.00891 AC: 9 AN: 1010

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Benign:1

Dec 21, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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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;