XM_047423927.1:c.-152+3548C>T

Variant names:

• chr9-214864-C-T
• rs2236547
• XM_047423927.1:c.-152+3548C>T

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+3548C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.22 in 1,604,274 control chromosomes in the GnomAD database, including 41,243 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.24 (4754 hom., cov: 34)
  • Exomes 𝑓: 0.22 (36489 hom.)
• Consequence: DOCK8 XM_047423927.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.0540

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=6.2680244E-4).
• BP6: Variant 9-214864-C-T is Benign according to our data. Variant chr9-214864-C-T is described in ClinVar as [Benign]. Clinvar id is 369626.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.377 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DOCK8	NM_203447.4	c.-113C>T		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.-113C>T		upstream_gene_variant		1	NM_203447.4	ENSP00000394888.3

Frequencies

GnomAD3 genomes AF: 0.244 AC: 37095 AN: 151916 Hom.: 4746 Cov.: 34

Gnomad AFR AF: 0.289

Gnomad AMI AF: 0.249

Gnomad AMR AF: 0.293

Gnomad ASJ AF: 0.252

Gnomad EAS AF: 0.391

Gnomad SAS AF: 0.337

Gnomad FIN AF: 0.175

Gnomad MID AF: 0.268

Gnomad NFE AF: 0.198

Gnomad OTH AF: 0.269

GnomAD3 exomes AF: 0.255 AC: 59015 AN: 231510 Hom.: 8292 AF XY: 0.253 AC XY: 32375 AN XY: 127742

Gnomad AFR exome AF: 0.286

Gnomad AMR exome AF: 0.353

Gnomad ASJ exome AF: 0.244

Gnomad EAS exome AF: 0.389

Gnomad SAS exome AF: 0.327

Gnomad FIN exome AF: 0.172

Gnomad NFE exome AF: 0.197

Gnomad OTH exome AF: 0.242

GnomAD4 exome AF: 0.217 AC: 315097 AN: 1452246 Hom.: 36489 Cov.: 105 AF XY: 0.220 AC XY: 159020 AN XY: 722444

Gnomad4 AFR exome AF: 0.295

Gnomad4 AMR exome AF: 0.347

Gnomad4 ASJ exome AF: 0.244

Gnomad4 EAS exome AF: 0.381

Gnomad4 SAS exome AF: 0.328

Gnomad4 FIN exome AF: 0.173

Gnomad4 NFE exome AF: 0.196

Gnomad4 OTH exome AF: 0.233

GnomAD4 genome AF: 0.244 AC: 37138 AN: 152028 Hom.: 4754 Cov.: 34 AF XY: 0.246 AC XY: 18250 AN XY: 74314

Gnomad4 AFR AF: 0.288

Gnomad4 AMR AF: 0.294

Gnomad4 ASJ AF: 0.252

Gnomad4 EAS AF: 0.391

Gnomad4 SAS AF: 0.337

Gnomad4 FIN AF: 0.175

Gnomad4 NFE AF: 0.198

Gnomad4 OTH AF: 0.277

Alfa AF: 0.207 Hom.: 4982

Bravo AF: 0.255

TwinsUK AF: 0.186 AC: 689

ALSPAC AF: 0.197 AC: 760

ESP6500AA AF: 0.278 AC: 1030

ESP6500EA AF: 0.185 AC: 1388

ExAC AF: 0.254 AC: 29793

Asia WGS AF: 0.395 AC: 1373 AN: 3468

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 14, 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. -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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 57% of patients studied by a panel of primary immunodeficiencies. Number of patients: 55. Only high quality variants are reported. -

Hyper-IgE syndrome Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.81	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	6.6
DANN	Benign	0.90
DEOGEN2	Benign	0.059	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.0060	N
LIST_S2	Benign	0.32	T
MetaRNN	Benign	0.00063	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.0	N
PROVEAN	Benign	-0.50	N
REVEL	Benign	0.097
Sift4G	Benign	0.46	T
Polyphen		0.0	B
Vest4		0.013
MPC		0.15
ClinPred		0.0027	T
GERP RS		3.5
Varity_R		0.13
gMVP		0.0061

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: rs2236547; hg19: chr9-214864; COSMIC: COSV66687989; COSMIC: COSV66687989;