rs767478064

Variant names:

• chr9-451994-TTTTTTTTTC-T
• rs767478064
• NM_203447.4:c.5962-16_5962-8delTTTTTTTTC

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP6_Very_Strong

The NM_203447.4(DOCK8):​c.5962-16_5962-8delTTTTTTTTC variant causes a splice region, 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, intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.64
• 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, G2P, Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen
• 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 -8 ACMG points.

• 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 VariationId is 536611.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_203447.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DOCK8	NM_203447.4	MANE Select	c.5962-16_5962-8delTTTTTTTTC		splice_region intron	N/A	NP_982272.2	Q8NF50-1
	DOCK8	NM_001193536.2		c.5758-16_5758-8delTTTTTTTTC		splice_region intron	N/A	NP_001180465.1	Q8NF50-3
	DOCK8	NM_001190458.2		c.5662-16_5662-8delTTTTTTTTC		splice_region intron	N/A	NP_001177387.1	Q8NF50-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DOCK8	ENST00000432829.7	TSL:1 MANE Select	c.5962-16_5962-8delTTTTTTTTC		splice_region intron	N/A	ENSP00000394888.3	Q8NF50-1
	DOCK8	ENST00000469391.5	TSL:1	c.5662-16_5662-8delTTTTTTTTC		splice_region intron	N/A	ENSP00000419438.1	Q8NF50-4
	DOCK8	ENST00000382329.2	TSL:1	c.5662-16_5662-8delTTTTTTTTC		splice_region intron	N/A	ENSP00000371766.2	A2A369

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

GnomAD2 exomes AF: 0.000269 AC: 13 AN: 48254 AF XY: 0.000225

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000324

Gnomad ASJ exome AF: 0.000304

Gnomad EAS exome AF: 0.000511

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000350

Gnomad OTH exome AF: 0.000835

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

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

African (AFR) AF: 0.00 AC: 0 AN: 12238

American (AMR) AF: 0.000168 AC: 3 AN: 17856

Ashkenazi Jewish (ASJ) AF: 0.000223 AC: 3 AN: 13480

East Asian (EAS) AF: 0.000129 AC: 3 AN: 23340

South Asian (SAS) AF: 0.000201 AC: 8 AN: 39808

European-Finnish (FIN) AF: 0.000217 AC: 5 AN: 23038

Middle Eastern (MID) AF: 0.000502 AC: 1 AN: 1992

European-Non Finnish (NFE) AF: 0.000276 AC: 91 AN: 329638

Other (OTH) AF: 0.000217 AC: 5 AN: 23058

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

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

African (AFR) AF: 0.000224 AC: 7 AN: 31290

American (AMR) AF: 0.000244 AC: 2 AN: 8190

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2336

East Asian (EAS) AF: 0.00 AC: 0 AN: 2958

South Asian (SAS) AF: 0.00 AC: 0 AN: 2928

European-Finnish (FIN) AF: 0.000951 AC: 4 AN: 4206

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 144

European-Non Finnish (NFE) AF: 0.00139 AC: 56 AN: 40318

Other (OTH) AF: 0.00 AC: 0 AN: 1194

⚠️ 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: 0.000552 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	Not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.6

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs767478064;

hg19: chr9-451994;