Genetic Variant DOCK8:p.Leu4Leu (chr9-214988-G-C) – ACMG Classification: Likely_benign (-1 pts)

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2BP4_ModerateBP7

The NM_203447.4(DOCK8):c.12G>C(p.Leu4Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. L4L) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

DOCK8
NM_203447.4 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.127

Publications

0 publications found

Variant links:

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 links:

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

DOCK8-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.11929917).

BP7

Synonymous conserved (PhyloP=0.127 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_203447.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DOCK8	NM_203447.4	MANE Select	c.12G>C	p.Leu4Leu	synonymous	Exon 1 of 48	NP_982272.2	Q8NF50-1
	DOCK8-AS1	NR_160804.1		n.763C>G		non_coding_transcript_exon	Exon 1 of 1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DOCK8	ENST00000432829.7	TSL:1 MANE Select	c.12G>C	p.Leu4Leu	synonymous	Exon 1 of 48	ENSP00000394888.3	Q8NF50-1
DOCK8-AS1	ENST00000382387.4	TSL:6	n.906C>G		non_coding_transcript_exon	Exon 1 of 1
DOCK8	ENST00000454469.6	TSL:2	n.121G>C		non_coding_transcript_exon	Exon 1 of 14

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

215616

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1447054

Hom.:

Cov.:

111

AF XY:

0.00

AC XY:

AN XY:

719718

African (AFR)

AF:

0.00

AC:

AN:

31818

American (AMR)

AF:

0.00

AC:

AN:

43942

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25756

East Asian (EAS)

AF:

0.00

AC:

AN:

38784

South Asian (SAS)

AF:

0.00

AC:

AN:

84788

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48110

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5702

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1108296

Other (OTH)

AF:

0.00

AC:

AN:

59858

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000869

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.48

CADD

Benign

(source)

DANN

Benign

0.38

DEOGEN2

Benign

0.0097

Eigen

Benign

-0.99

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.51

LIST_S2

Benign

0.44

M_CAP

Benign

0.022

MetaRNN

Benign

0.12

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

PhyloP100

0.13

PROVEAN

Uncertain

-2.6

REVEL

Benign

0.12

Sift4G

Benign

0.34

Polyphen

0.38

Vest4

0.27

MutPred

0.16

Loss of MoRF binding (P = 0.0412)

MVP

0.18

MPC

0.17

ClinPred

0.19

GERP RS

-2.7

PromoterAI

-0.034

Neutral

(source)

Varity_R

0.73

gMVP

0.015

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over