rs767478064

chr9-451994-TTTTTTTTTC-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 2P and 12B. PM2 BP6_Very_Strong BS1

The NM_203447.4(DOCK8):c.5962-16_5962-8del variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000325 in 578,636 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00073 (0 hom., cov: 21)
  • Exomes 𝑓: 0.00025 (0 hom.)
• Consequence: DOCK8 NM_203447.4 splice_region, splice_polypyrimidine_tract, intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.64

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]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 9-451994-TTTTTTTTTC-T is Benign according to our data. Variant chr9-451994-TTTTTTTTTC-T is described in ClinVar as [Likely_benign]. Clinvar id is 536611.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-451994-TTTTTTTTTC-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000733 (69/94188) while in subpopulation NFE AF= 0.00139 (56/40318). AF 95% confidence interval is 0.0011. There are 0 homozygotes in gnomad4. There are 26 alleles in male gnomad4 subpopulation. Median coverage is 21. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DOCK8	NM_203447.4	c.5962-16_5962-8del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000432829.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DOCK8	ENST00000432829.7	c.5962-16_5962-8del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_203447.4

Frequencies

GnomAD3 genomes AF: 0.000733 AC: 69 AN: 94158 Hom.: 0 Cov.: 21

Gnomad AFR AF: 0.000224

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000244

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000951

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00139

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000246 AC: 119 AN: 484448 Hom.: 0 AF XY: 0.000270 AC XY: 70 AN XY: 258796

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000168

Gnomad4 ASJ exome AF: 0.000223

Gnomad4 EAS exome AF: 0.000129

Gnomad4 SAS exome AF: 0.000201

Gnomad4 FIN exome AF: 0.000217

Gnomad4 NFE exome AF: 0.000276

Gnomad4 OTH exome AF: 0.000217

GnomAD4 genome AF: 0.000733 AC: 69 AN: 94188 Hom.: 0 Cov.: 21 AF XY: 0.000582 AC XY: 26 AN XY: 44658

Gnomad4 AFR AF: 0.000224

Gnomad4 AMR AF: 0.000244

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000951

Gnomad4 NFE AF: 0.00139

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000552 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Apr 01, 2023

DOCK8: BP4 -

Autosomal recessive hyper-IgE syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Sep 04, 2023

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs767478064; hg19: chr9-451994;