rs117610764

chr9-386414-A-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_203447.4(DOCK8):c.2862A>T(p.Pro954=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00817 in 1,613,488 control chromosomes in the GnomAD database, including 92 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0066 (12 hom., cov: 33)
  • Exomes 𝑓: 0.0083 (80 hom.)
• Consequence: DOCK8 NM_203447.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.281

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 9-386414-A-T is Benign according to our data. Variant chr9-386414-A-T is described in ClinVar as [Benign]. Clinvar id is 366955.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.281 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00657 (1000/152278) while in subpopulation SAS AF= 0.0207 (100/4822). AF 95% confidence interval is 0.0174. There are 12 homozygotes in gnomad4. There are 514 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DOCK8	NM_203447.4	c.2862A>T	p.Pro954=	synonymous_variant	23/48	ENST00000432829.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DOCK8	ENST00000432829.7	c.2862A>T	p.Pro954=	synonymous_variant	23/48	1	NM_203447.4

Frequencies

GnomAD3 genomes AF: 0.00658 AC: 1001 AN: 152160 Hom.: 12 Cov.: 33

Gnomad AFR AF: 0.00140

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00648

Gnomad ASJ AF: 0.0257

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0207

Gnomad FIN AF: 0.00791

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00810

Gnomad OTH AF: 0.00670

GnomAD3 exomes AF: 0.00879 AC: 2210 AN: 251328 Hom.: 24 AF XY: 0.00995 AC XY: 1351 AN XY: 135844

Gnomad AFR exome AF: 0.000985

Gnomad AMR exome AF: 0.00376

Gnomad ASJ exome AF: 0.0258

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0223

Gnomad FIN exome AF: 0.00776

Gnomad NFE exome AF: 0.00780

Gnomad OTH exome AF: 0.0108

GnomAD4 exome AF: 0.00834 AC: 12183 AN: 1461210 Hom.: 80 Cov.: 31 AF XY: 0.00882 AC XY: 6410 AN XY: 726898

Gnomad4 AFR exome AF: 0.000777

Gnomad4 AMR exome AF: 0.00405

Gnomad4 ASJ exome AF: 0.0264

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0216

Gnomad4 FIN exome AF: 0.00720

Gnomad4 NFE exome AF: 0.00761

Gnomad4 OTH exome AF: 0.00877

GnomAD4 genome AF: 0.00657 AC: 1000 AN: 152278 Hom.: 12 Cov.: 33 AF XY: 0.00690 AC XY: 514 AN XY: 74460

Gnomad4 AFR AF: 0.00140

Gnomad4 AMR AF: 0.00647

Gnomad4 ASJ AF: 0.0257

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0207

Gnomad4 FIN AF: 0.00791

Gnomad4 NFE AF: 0.00810

Gnomad4 OTH AF: 0.00663

Alfa AF: 0.00948 Hom.: 4

Bravo AF: 0.00581

EpiCase AF: 0.00965

EpiControl AF: 0.00777

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	May 15, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	Pro954Pro in exon 23 of DOCK8: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue and is not located wit hin the splice consensus sequence. It has been identified in 1.0% (83/8600) of E uropean American chromosomes from a broad population by the NHLBI Exome Sequenci ng Project (http://evs.gs.washington.edu/EVS; dbSNP rs117610764). -

Combined immunodeficiency due to DOCK8 deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Autosomal recessive hyper-IgE syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
Cadd	Benign	3.5
Dann	Benign	0.79

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs117610764; hg19: chr9-386414; COSMIC: COSV101210080;