rs771454295

Variant names:

• chr9-451971-ATATATATTTTTTTTTTTTTTTT-A
• rs771454295
• NM_203447.4:c.5962-38_5962-17delATATATTTTTTTTTTTTTTTTT

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.5962-38_5962-17delATATATTTTTTTTTTTTTTTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000994 in 401,354 control chromosomes in the GnomAD database, including 4 homozygotes. 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.0049 (1 hom., cov: 10)
  • Exomes 𝑓: 0.00026 (3 hom.)
• Consequence: DOCK8 NM_203447.4 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.06
• 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 9-451971-ATATATATTTTTTTTTTTTTTTT-A is Benign according to our data. Variant chr9-451971-ATATATATTTTTTTTTTTTTTTT-A is described in ClinVar as [Likely_benign]. Clinvar id is 445540.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00491 (311/63362) while in subpopulation AFR AF = 0.0157 (287/18236). AF 95% confidence interval is 0.0142. There are 1 homozygotes in GnomAd4. There are 149 alleles in the male GnomAd4 subpopulation. Median coverage is 10. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DOCK8	NM_203447.4	c.5962-38_5962-17delATATATTTTTTTTTTTTTTTTT		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.5962-39_5962-18delTATATATTTTTTTTTTTTTTTT		intron_variant	Intron 45 of 47	1	NM_203447.4	ENSP00000394888.3

Frequencies

GnomAD3 genomes AF: 0.00491 AC: 311 AN: 63362 Hom.: 1 Cov.: 10

Gnomad AFR AF: 0.0158

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00514

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000600

Gnomad OTH AF: 0.00289

GnomAD2 exomes AF: 0.000198 AC: 11 AN: 55528 AF XY: 0.000121

Gnomad AFR exome AF: 0.00759

Gnomad AMR exome AF: 0.000227

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000737

GnomAD4 exome AF: 0.000260 AC: 88 AN: 337992 Hom.: 3 AF XY: 0.000180 AC XY: 34 AN XY: 188628

African (AFR) AF: 0.0128 AC: 70 AN: 5484

American (AMR) AF: 0.000373 AC: 6 AN: 16072

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 11396

East Asian (EAS) AF: 0.00 AC: 0 AN: 20806

South Asian (SAS) AF: 0.00 AC: 0 AN: 33818

European-Finnish (FIN) AF: 0.0000564 AC: 1 AN: 17740

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1360

European-Non Finnish (NFE) AF: 0.00000467 AC: 1 AN: 214202

Other (OTH) AF: 0.000584 AC: 10 AN: 17114

GnomAD4 genome AF: 0.00491 AC: 311 AN: 63362 Hom.: 1 Cov.: 10 AF XY: 0.00528 AC XY: 149 AN XY: 28210

African (AFR) AF: 0.0157 AC: 287 AN: 18236

American (AMR) AF: 0.00514 AC: 20 AN: 3890

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1552

East Asian (EAS) AF: 0.00 AC: 0 AN: 1896

South Asian (SAS) AF: 0.00 AC: 0 AN: 1428

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1578

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 134

European-Non Finnish (NFE) AF: 0.0000600 AC: 2 AN: 33320

Other (OTH) AF: 0.00288 AC: 2 AN: 694

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 19, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Benign:1

Jan 23, 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		3.1

Splicing

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

Other links and lift over

dbSNP: rs771454295; hg19: chr9-451971;