chr9-214919-C-T

Position:

• chr9-214919-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_203447.4(DOCK8):​c.-58C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00134 in 1,604,366 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0012 (1 hom., cov: 34)
  • Exomes 𝑓: 0.0014 (3 hom.)
• Consequence: DOCK8 NM_203447.4 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.00400

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:):

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0055783987).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00117 (178/152284) while in subpopulation NFE AF= 0.00132 (90/68000). AF 95% confidence interval is 0.0011. There are 1 homozygotes in gnomad4. There are 105 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DOCK8	NM_203447.4	c.-58C>T		5_prime_UTR_variant	1/48	ENST00000432829.7	NP_982272.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DOCK8	ENST00000432829	c.-58C>T		5_prime_UTR_variant	1/48	1	NM_203447.4	ENSP00000394888.3

Frequencies

GnomAD3 genomes AF: 0.00117 AC: 178 AN: 152176 Hom.: 1 Cov.: 34

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00650

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00132

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.00137 AC: 309 AN: 226010 Hom.: 0 AF XY: 0.00138 AC XY: 173 AN XY: 125406

Gnomad AFR exome AF: 0.000168

Gnomad AMR exome AF: 0.0000306

Gnomad ASJ exome AF: 0.00117

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00631

Gnomad NFE exome AF: 0.00155

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.00136 AC: 1972 AN: 1452082 Hom.: 3 Cov.: 111 AF XY: 0.00128 AC XY: 927 AN XY: 722376

Gnomad4 AFR exome AF: 0.000156

Gnomad4 AMR exome AF: 0.0000682

Gnomad4 ASJ exome AF: 0.00108

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00612

Gnomad4 NFE exome AF: 0.00140

Gnomad4 OTH exome AF: 0.00108

GnomAD4 genome AF: 0.00117 AC: 178 AN: 152284 Hom.: 1 Cov.: 34 AF XY: 0.00141 AC XY: 105 AN XY: 74464

Gnomad4 AFR AF: 0.000168

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00231

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00650

Gnomad4 NFE AF: 0.00132

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.000990 Hom.: 0

Bravo AF: 0.000820

ESP6500AA AF: 0.000267 AC: 1

ESP6500EA AF: 0.00133 AC: 10

ExAC AF: 0.00149 AC: 175

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Combined immunodeficiency due to DOCK8 deficiency Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	8.7
DANN	Benign	0.82
DEOGEN2	Benign	0.046	T
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.071	N
LIST_S2	Benign	0.39	T
M_CAP	Benign	0.0038	T
MetaRNN	Benign	0.0056	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
PROVEAN	Uncertain	-3.5	D
REVEL	Benign	0.093
Sift4G	Pathogenic	0.0	D
Polyphen		0.82	P
Vest4		0.032
MVP		0.15
MPC		0.40
ClinPred		0.058	T
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.37
gMVP		0.017

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: rs144097790; hg19: chr9-214919;