Genetic Variant DOCK8:c.5962-21_5962-9delTTTTTTTTTTTTT (chr9-451977-ATTTTTTTTTTTTT-A) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS1

The NM_203447.4(DOCK8):c.5962-21_5962-9delTTTTTTTTTTTTT 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. There are indicators that this mutation may affect the branch point..

Frequency

Genomes: 𝑓 0.00085 ( 0 hom., cov: 0)

Exomes 𝑓: 0.0020 ( 4 hom. )

Failed GnomAD Quality Control

Consequence

DOCK8
NM_203447.4 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.34

Publications

1 publications found

Variant links:

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

DOCK8 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000855 (71/83052) while in subpopulation SAS AF = 0.00457 (12/2624). AF 95% confidence interval is 0.00264. There are 0 homozygotes in GnomAd4. There are 34 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 link	c.5962-21_5962-9delTTTTTTTTTTTTT		intron_variant	Intron 45 of 47	ENST00000432829.7	NP_982272.2	Q8NF50-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DOCK8	ENST00000432829.7 link	c.5962-33_5962-21delTTTTTTTTTTTTT		intron_variant	Intron 45 of 47	1	NM_203447.4	ENSP00000394888.3		Q8NF50-1

Frequencies

GnomAD3 genomes

AF:

0.000855

AC:

AN:

83068

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00143

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000680

Gnomad ASJ

AF:

0.000395

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00454

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000591

Gnomad OTH

AF:

0.000996

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00202

AC:

205

AN:

101320

Hom.:

AF XY:

0.00200

AC XY:

122

AN XY:

60938

show subpopulations

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

African (AFR)

AF:

0.00674

AC:

AN:

1484

American (AMR)

AF:

0.00215

AC:

AN:

4188

Ashkenazi Jewish (ASJ)

AF:

0.00111

AC:

AN:

2706

East Asian (EAS)

AF:

0.000596

AC:

AN:

5036

South Asian (SAS)

AF:

0.00319

AC:

AN:

8476

European-Finnish (FIN)

AF:

0.00221

AC:

AN:

4066

Middle Eastern (MID)

AF:

0.00562

AC:

AN:

356

European-Non Finnish (NFE)

AF:

0.00191

AC:

134

AN:

70042

Other (OTH)

AF:

0.00161

AC:

AN:

4966

⚠️ 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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.350

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000855

AC:

AN:

83052

Hom.:

Cov.:

AF XY:

0.000904

AC XY:

AN XY:

37620

show subpopulations

African (AFR)

AF:

0.00149

AC:

AN:

17490

American (AMR)

AF:

0.000680

AC:

AN:

7358

Ashkenazi Jewish (ASJ)

AF:

0.000395

AC:

AN:

2534

East Asian (EAS)

AF:

0.00

AC:

AN:

3506

South Asian (SAS)

AF:

0.00457

AC:

AN:

2624

European-Finnish (FIN)

AF:

0.00

AC:

AN:

2100

Middle Eastern (MID)

AF:

0.00

AC:

AN:

126

European-Non Finnish (NFE)

AF:

0.000591

AC:

AN:

45694

Other (OTH)

AF:

0.00

AC:

AN:

1012

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.529

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

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

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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9-451977-ATTTTTTTTTTTTTTTTT-ATTTT

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over