9-214991-G-A

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS1

The NM_203447.4(DOCK8):c.15G>A(p.Pro5=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000444 in 1,597,620 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00072 (1 hom., cov: 34)
  • Exomes 𝑓: 0.00042 (2 hom.)
• Consequence: DOCK8 NM_203447.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.54

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.01509881).
• BP6: Variant 9-214991-G-A is Benign according to our data. Variant chr9-214991-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 712348.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.54 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000716 (109/152260) while in subpopulation NFE AF= 0.00116 (79/68006). AF 95% confidence interval is 0.000955. There are 1 homozygotes in gnomad4. There are 53 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DOCK8	NM_203447.4	c.15G>A	p.Pro5=	synonymous_variant	1/48	ENST00000432829.7
DOCK8-AS1	NR_160804.1	n.760C>T		non_coding_transcript_exon_variant	1/1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DOCK8	ENST00000432829.7	c.15G>A	p.Pro5=	synonymous_variant	1/48	1	NM_203447.4
DOCK8-AS1	ENST00000648587.1	n.751C>T		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes AF: 0.000716 AC: 109 AN: 152150 Hom.: 1 Cov.: 34

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00264

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00116

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000559 AC: 119 AN: 212792 Hom.: 0 AF XY: 0.000588 AC XY: 70 AN XY: 119100

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000615

Gnomad ASJ exome AF: 0.000221

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00218

Gnomad NFE exome AF: 0.000820

Gnomad OTH exome AF: 0.000190

GnomAD4 exome AF: 0.000415 AC: 600 AN: 1445360 Hom.: 2 Cov.: 110 AF XY: 0.000422 AC XY: 303 AN XY: 718822

Gnomad4 AFR exome AF: 0.0000315

Gnomad4 AMR exome AF: 0.0000457

Gnomad4 ASJ exome AF: 0.000233

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000118

Gnomad4 FIN exome AF: 0.00230

Gnomad4 NFE exome AF: 0.000418

Gnomad4 OTH exome AF: 0.000301

GnomAD4 genome AF: 0.000716 AC: 109 AN: 152260 Hom.: 1 Cov.: 34 AF XY: 0.000712 AC XY: 53 AN XY: 74460

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00264

Gnomad4 NFE AF: 0.00116

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000569 Hom.: 0

Bravo AF: 0.000336

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000413 AC: 3

ExAC AF: 0.000505 AC: 58

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Feb 01, 2024

DOCK8: BP4, BP7 -

DOCK8-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 17, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Autosomal recessive hyper-IgE syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 02, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.54
Cadd	Benign	7.6
Dann	Benign	0.87
DEOGEN2	Benign	0.075	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.47	T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.015	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	0.79	D;N;N
PROVEAN	Pathogenic	-7.0	D
REVEL	Benign	0.18
Sift4G	Uncertain	0.039	D
Polyphen		1.0	D
Vest4		0.20
MVP		0.22
MPC		0.18
ClinPred		0.20	T
GERP RS		-5.1
Varity_R		0.52
gMVP		0.027

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: rs148276394; hg19: chr9-214991;