chr9-463655-C-A

Variant names:

• chr9-463655-C-A
• rs79568455
• NM_203447.4:c.6207C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PVS1_Moderate

The NM_203447.4(DOCK8):​c.6207C>A​(p.Tyr2069*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0078 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: DOCK8 NM_203447.4 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.16
• Publications: 9 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-AS2 (HGNC:55822): (DOCK8 antisense RNA 2)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0148 CDS is truncated, and there are 0 pathogenic variants in the truncated region.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DOCK8	NM_203447.4	c.6207C>A	p.Tyr2069*	stop_gained	Exon 47 of 48	ENST00000432829.7	NP_982272.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DOCK8	ENST00000432829.7	c.6207C>A	p.Tyr2069*	stop_gained	Exon 47 of 48	1	NM_203447.4	ENSP00000394888.3

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151918 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0668 AC: 13201 AN: 197748 AF XY: 0.0667

Gnomad AFR exome AF: 0.118

Gnomad AMR exome AF: 0.0689

Gnomad ASJ exome AF: 0.0214

Gnomad EAS exome AF: 0.0959

Gnomad FIN exome AF: 0.0877

Gnomad NFE exome AF: 0.0676

Gnomad OTH exome AF: 0.0347

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00785 AC: 11245 AN: 1432722 Hom.: 0 Cov.: 32 AF XY: 0.00870 AC XY: 6172 AN XY: 709782

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

African (AFR) AF: 0.0176 AC: 577 AN: 32822

American (AMR) AF: 0.0636 AC: 2625 AN: 41288

Ashkenazi Jewish (ASJ) AF: 0.00932 AC: 230 AN: 24676

East Asian (EAS) AF: 0.0375 AC: 1451 AN: 38744

South Asian (SAS) AF: 0.0110 AC: 892 AN: 81284

European-Finnish (FIN) AF: 0.0250 AC: 1209 AN: 48384

Middle Eastern (MID) AF: 0.00325 AC: 18 AN: 5534

European-Non Finnish (NFE) AF: 0.00356 AC: 3918 AN: 1100620

Other (OTH) AF: 0.00547 AC: 325 AN: 59370

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000197 AC: 3 AN: 152028 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74286

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

African (AFR) AF: 0.00 AC: 0 AN: 41538

American (AMR) AF: 0.00 AC: 0 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3458

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5148

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 288

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67866

Other (OTH) AF: 0.00 AC: 0 AN: 2106

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.000758 Hom.: 0

ExAC AF: 0.104 AC: 12509

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	39
DANN	Uncertain	1.0
Eigen	Pathogenic	0.74
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.95	D
PhyloP100		1.2
Vest4		0.72
GERP RS		5.0
Mutation Taster		=6/194	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs79568455; hg19: chr9-463655; COSMIC: COSV66617383; COSMIC: COSV66617383;