Genetic Variant NM_203447.4:c.5962-23_5962-9delTTTTTTTTTTTTTTT (chr9-451977-ATTTTTTTTTTTTTTT-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP6_Moderate

The NM_203447.4(DOCK8):c.5962-23_5962-9delTTTTTTTTTTTTTTT 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. Variant has been reported in ClinVar as Likely benign (★). There are indicators that this mutation may affect the branch point..

Frequency

Genomes: 𝑓 0.00051 ( 0 hom., cov: 0)

Exomes 𝑓: 0.00085 ( 3 hom. )

Failed GnomAD Quality Control

Consequence

DOCK8
NM_203447.4 intron

Scores

Not classified

Clinical Significance

Likely benign criteria provided, single submitter B:1

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 -2 ACMG points.

BP6

Variant 9-451977-ATTTTTTTTTTTTTTT-A is Benign according to our data. Variant chr9-451977-ATTTTTTTTTTTTTTT-A is described in ClinVar as [Likely_benign]. Clinvar id is 1669779.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DOCK8	NM_203447.4 link	c.5962-23_5962-9delTTTTTTTTTTTTTTT		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_5962-19delTTTTTTTTTTTTTTT		intron_variant	Intron 45 of 47	1	NM_203447.4	ENSP00000394888.3		Q8NF50-1

Frequencies

GnomAD3 genomes

AF:

0.000506

AC:

AN:

83070

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000515

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000680

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000756

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000569

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000848

AC:

AN:

101458

Hom.:

AF XY:

0.000836

AC XY:

AN XY:

61022

show subpopulations

African (AFR)

AF:

0.00336

AC:

AN:

1488

American (AMR)

AF:

0.000955

AC:

AN:

4190

Ashkenazi Jewish (ASJ)

AF:

0.000369

AC:

AN:

2708

East Asian (EAS)

AF:

0.000199

AC:

AN:

5036

South Asian (SAS)

AF:

0.00247

AC:

AN:

8494

European-Finnish (FIN)

AF:

0.00

AC:

AN:

4072

Middle Eastern (MID)

AF:

0.00

AC:

AN:

356

European-Non Finnish (NFE)

AF:

0.000727

AC:

AN:

70136

Other (OTH)

AF:

0.000603

AC:

AN:

4978

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.435

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000506

AC:

AN:

83070

Hom.:

Cov.:

AF XY:

0.000346

AC XY:

AN XY:

37616

show subpopulations

African (AFR)

AF:

0.000515

AC:

AN:

17474

American (AMR)

AF:

0.000680

AC:

AN:

7354

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2534

East Asian (EAS)

AF:

0.00

AC:

AN:

3520

South Asian (SAS)

AF:

0.000756

AC:

AN:

2646

European-Finnish (FIN)

AF:

0.00

AC:

AN:

2100

Middle Eastern (MID)

AF:

0.00

AC:

AN:

132

European-Non Finnish (NFE)

AF:

0.000569

AC:

AN:

45698

Other (OTH)

AF:

0.00

AC:

AN:

1004

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.579

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Benign:1

Jan 07, 2025

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

=96/4

polymorphism

(source)

Splicing

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

Publications

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NM_203447.4:c.5962-23_5962-9delTTTTTTTTTTTTTTT

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over