Genetic Variant DOCK8:c.5962-14_5962-9delTTTTTT (chr9-451977-ATTTTTT-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.5962-14_5962-9delTTTTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. 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 0.00063 ( 0 hom., cov: 10)

Exomes 𝑓: 0.00064 ( 1 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 eas. GnomAd4 allele frequency = 0.000626 (52/83050) while in subpopulation EAS AF = 0.00885 (31/3502). AF 95% confidence interval is 0.00641. There are 0 homozygotes in GnomAd4. There are 29 alleles in the male GnomAd4 subpopulation. Median coverage is 10. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DOCK8	NM_203447.4 link	c.5962-14_5962-9delTTTTTT		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_5962-28delTTTTTT		intron_variant	Intron 45 of 47	1	NM_203447.4	ENSP00000394888.3		Q8NF50-1

Frequencies

GnomAD3 genomes

AF:

0.000626

AC:

AN:

83066

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000286

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000408

Gnomad ASJ

AF:

0.00237

Gnomad EAS

AF:

0.00882

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000476

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000875

Gnomad OTH

AF:

0.00199

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000641

AC:

AN:

101386

Hom.:

AF XY:

0.000558

AC XY:

AN XY:

60974

show subpopulations

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

African (AFR)

AF:

0.000673

AC:

AN:

1486

American (AMR)

AF:

0.00144

AC:

AN:

4178

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2704

East Asian (EAS)

AF:

0.00580

AC:

AN:

5000

South Asian (SAS)

AF:

0.000471

AC:

AN:

8484

European-Finnish (FIN)

AF:

0.000491

AC:

AN:

4072

Middle Eastern (MID)

AF:

0.00

AC:

AN:

356

European-Non Finnish (NFE)

AF:

0.000285

AC:

AN:

70132

Other (OTH)

AF:

0.000603

AC:

AN:

4974

⚠️ 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: 0.352

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000626

AC:

AN:

83050

Hom.:

Cov.:

AF XY:

0.000771

AC XY:

AN XY:

37622

show subpopulations

African (AFR)

AF:

0.000286

AC:

AN:

17490

American (AMR)

AF:

0.000408

AC:

AN:

7358

Ashkenazi Jewish (ASJ)

AF:

0.00237

AC:

AN:

2534

East Asian (EAS)

AF:

0.00885

AC:

AN:

3502

South Asian (SAS)

AF:

0.00

AC:

AN:

2624

European-Finnish (FIN)

AF:

0.000476

AC:

AN:

2100

Middle Eastern (MID)

AF:

0.00

AC:

AN:

126

European-Non Finnish (NFE)

AF:

0.0000875

AC:

AN:

45694

Other (OTH)

AF:

0.00197

AC:

AN:

1014

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.445

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

Splicing

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

Publications

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9-451977-ATTTTTTTTTTTTTTTTT-ATTTTTTTTTTT

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