Genetic Variant DOCK4:p.Arg853His (chr7-111847042-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001363540.2(DOCK4):c.2558G>A(p.Arg853His) variant causes a missense change. The variant allele was found at a frequency of 0.00705 in 1,613,734 control chromosomes in the GnomAD database, including 726 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0096 ( 65 hom., cov: 33)

Exomes 𝑓: 0.0068 ( 661 hom. )

Consequence

DOCK4
NM_001363540.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.53

Publications

15 publications found

Variant links:

Genes affected

DOCK4 (HGNC:19192): (dedicator of cytokinesis 4) This gene is a member of the dedicator of cytokinesis (DOCK) family and encodes a protein with a DHR-1 (CZH-1) domain, a DHR-2 (CZH-2) domain and an SH3 domain. This membrane-associated, cytoplasmic protein functions as a guanine nucleotide exchange factor and is involved in regulation of adherens junctions between cells. Mutations in this gene have been associated with ovarian, prostate, glioma, and colorectal cancers. Alternatively spliced variants which encode different protein isoforms have been described, but only one has been fully characterized. [provided by RefSeq, Jul 2008]

DOCK4 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.002487719).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.11 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DOCK4	NM_001363540.2 link	c.2558G>A	p.Arg853His	missense_variant	Exon 24 of 53	ENST00000428084.6	NP_001350469.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
DOCK4	ENST00000428084.6 link	c.2558G>A	p.Arg853His	missense_variant	Exon 24 of 53	5	NM_001363540.2	ENSP00000410746.1	Q8N1I0-3
DOCK4	ENST00000437633.6 link	c.2558G>A	p.Arg853His	missense_variant	Exon 24 of 52	1		ENSP00000404179.1	Q8N1I0-1
DOCK4	ENST00000423057.6 link	c.911G>A	p.Arg304His	missense_variant	Exon 8 of 36	1		ENSP00000412834.1	H0Y7H7
DOCK4	ENST00000445943.5 link	c.2519G>A	p.Arg840His	missense_variant	Exon 23 of 53	5		ENSP00000397412.1	H0Y599

Frequencies

GnomAD3 genomes

AF:

0.00955

AC:

1453

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000989

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0468

Gnomad ASJ

AF:

0.00231

Gnomad EAS

AF:

0.118

Gnomad SAS

AF:

0.00290

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000735

Gnomad OTH

AF:

0.00717

GnomAD2 exomes

AF:

0.0178

AC:

4427

AN:

249028

AF XY:

0.0150

show subpopulations

Gnomad AFR exome

AF:

0.000517

Gnomad AMR exome

AF:

0.0576

Gnomad ASJ exome

AF:

0.00219

Gnomad EAS exome

AF:

0.123

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000727

Gnomad OTH exome

AF:

0.0112

GnomAD4 exome

AF:

0.00679

AC:

9923

AN:

1461462

Hom.:

661

Cov.:

AF XY:

0.00637

AC XY:

4630

AN XY:

727024

show subpopulations

African (AFR)

AF:

0.000508

AC:

AN:

33476

American (AMR)

AF:

0.0553

AC:

2474

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.00168

AC:

AN:

26124

East Asian (EAS)

AF:

0.155

AC:

6145

AN:

39676

South Asian (SAS)

AF:

0.00172

AC:

148

AN:

86250

European-Finnish (FIN)

AF:

0.0000749

AC:

AN:

53396

Middle Eastern (MID)

AF:

0.000867

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.000591

AC:

657

AN:

1111716

Other (OTH)

AF:

0.00711

AC:

429

AN:

60350

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

Heterozygous variant carriers

428

857

1285

1714

2142

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

136

272

408

544

680

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00958

AC:

1459

AN:

152272

Hom.:

Cov.:

AF XY:

0.0110

AC XY:

821

AN XY:

74450

show subpopulations

African (AFR)

AF:

0.000986

AC:

AN:

41572

American (AMR)

AF:

0.0472

AC:

721

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00231

AC:

AN:

3470

East Asian (EAS)

AF:

0.118

AC:

610

AN:

5180

South Asian (SAS)

AF:

0.00291

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10600

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000735

AC:

AN:

68024

Other (OTH)

AF:

0.00710

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

136

204

272

340

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00452

Hom.:

Bravo

AF:

0.0124

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.00153

AC:

ESP6500EA

AF:

0.000361

AC:

ExAC

AF:

0.0156

AC:

1884

Asia WGS

AF:

0.0440

AC:

154

AN:

3478

EpiCase

AF:

0.00115

EpiControl

AF:

0.000711

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.12

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.079

.;T;T

Eigen

Uncertain

0.34

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.95

D;D;D

MetaRNN

Benign

0.0025

T;T;T

MetaSVM

Benign

-1.2

MutationAssessor

Benign

1.4

L;L;.

PhyloP100

4.5

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-1.1

N;N;.

REVEL

Benign

0.19

Sift

Benign

0.10

T;T;.

Sift4G

Benign

0.21

T;T;T

Polyphen

0.014

.;B;.

Vest4

0.086

MPC

0.46

ClinPred

0.012

GERP RS

6.0

Varity_R

0.11

gMVP

0.41

Mutation Taster

=95/5

polymorphism (auto)

(source)

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over