9-214804-A-G

Variant names:

• chr9-214804-A-G
• rs76707254
• XM_047423927.1:c.-152+3488A>G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The XM_047423927.1(DOCK8):​c.-152+3488A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.119 in 1,587,796 control chromosomes in the GnomAD database, including 14,046 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1413 hom., cov: 34)
  • Exomes 𝑓: 0.12 (12633 hom.)
• Consequence: DOCK8 XM_047423927.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.114

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-AS1 (HGNC:26436): (DOCK8 antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003623575).
• BP6: Variant 9-214804-A-G is Benign according to our data. Variant chr9-214804-A-G is described in ClinVar as [Benign]. Clinvar id is 674418.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.351 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DOCK8	NM_203447.4	c.-173A>G		upstream_gene_variant		ENST00000432829.7	NP_982272.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DOCK8	ENST00000432829.7	c.-173A>G		upstream_gene_variant		1	NM_203447.4	ENSP00000394888.3

Frequencies

GnomAD3 genomes AF: 0.118 AC: 17856 AN: 151732 Hom.: 1405 Cov.: 34

Gnomad AFR AF: 0.0664

Gnomad AMI AF: 0.183

Gnomad AMR AF: 0.204

Gnomad ASJ AF: 0.132

Gnomad EAS AF: 0.365

Gnomad SAS AF: 0.219

Gnomad FIN AF: 0.0900

Gnomad MID AF: 0.159

Gnomad NFE AF: 0.105

Gnomad OTH AF: 0.150

GnomAD3 exomes AF: 0.153 AC: 31417 AN: 204968 Hom.: 3253 AF XY: 0.151 AC XY: 17184 AN XY: 113978

Gnomad AFR exome AF: 0.0562

Gnomad AMR exome AF: 0.273

Gnomad ASJ exome AF: 0.121

Gnomad EAS exome AF: 0.341

Gnomad SAS exome AF: 0.204

Gnomad FIN exome AF: 0.0879

Gnomad NFE exome AF: 0.0970

Gnomad OTH exome AF: 0.143

GnomAD4 exome AF: 0.119 AC: 171299 AN: 1435954 Hom.: 12633 Cov.: 91 AF XY: 0.122 AC XY: 86856 AN XY: 713296

Gnomad4 AFR exome AF: 0.0599

Gnomad4 AMR exome AF: 0.267

Gnomad4 ASJ exome AF: 0.125

Gnomad4 EAS exome AF: 0.355

Gnomad4 SAS exome AF: 0.207

Gnomad4 FIN exome AF: 0.0942

Gnomad4 NFE exome AF: 0.101

Gnomad4 OTH exome AF: 0.133

GnomAD4 genome AF: 0.118 AC: 17878 AN: 151842 Hom.: 1413 Cov.: 34 AF XY: 0.122 AC XY: 9051 AN XY: 74232

Gnomad4 AFR AF: 0.0662

Gnomad4 AMR AF: 0.205

Gnomad4 ASJ AF: 0.132

Gnomad4 EAS AF: 0.365

Gnomad4 SAS AF: 0.219

Gnomad4 FIN AF: 0.0900

Gnomad4 NFE AF: 0.105

Gnomad4 OTH AF: 0.159

Alfa AF: 0.107 Hom.: 306

Bravo AF: 0.125

TwinsUK AF: 0.0968 AC: 359

ALSPAC AF: 0.102 AC: 392

ESP6500AA AF: 0.0478 AC: 169

ESP6500EA AF: 0.0862 AC: 592

ExAC AF: 0.142 AC: 16427

Asia WGS AF: 0.327 AC: 1137 AN: 3470

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 16, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not specified Benign:1

Nov 12, 2023

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 42% of patients studied by a panel of primary immunodeficiencies. Number of patients: 40. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.81	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	14
DANN	Benign	0.50
DEOGEN2	Benign	0.048	T
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.016	N
LIST_S2	Benign	0.14	T
MetaRNN	Benign	0.0036	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.0	N
PROVEAN	Benign	1.5	N
REVEL	Benign	0.034
Sift4G	Benign	0.70	T
Polyphen		0.0	B
Vest4		0.023
MPC		0.16
ClinPred		0.0046	T
GERP RS		2.4
Varity_R		0.070
gMVP		0.0075

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs76707254; hg19: chr9-214804; COSMIC: COSV66688130; COSMIC: COSV66688130;