3-51361872-A-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_004947.5(DOCK3):c.5020A>T(p.Met1674Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00145 in 1,613,104 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0015 ( 2 hom. )

Consequence

DOCK3
NM_004947.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:2B:1

Conservation

PhyloP100: 3.25

Publications

5 publications found

Variant links:

Genes affected

DOCK3 (HGNC:2989): (dedicator of cytokinesis 3) This gene is specifically expressed in the central nervous system (CNS). It encodes a member of the DOCK (dedicator of cytokinesis) family of guanine nucleotide exchange factors (GEFs). This protein, dedicator of cytokinesis 3 (DOCK3), is also known as modifier of cell adhesion (MOCA) and presenilin-binding protein (PBP). The DOCK3 and DOCK1, -2 and -4 share several conserved amino acids in their DHR-2 (DOCK homology region 2) domains that are required for GEF activity, and bind directly to WAVE proteins [Wiskott-Aldrich syndrome protein (WASP) family Verprolin-homologous proteins] via their DHR-1 domains. The DOCK3 induces axonal outgrowth in CNS by stimulating membrane recruitment of the WAVE complex and activating the small G protein Rac1. This gene is associated with an attention deficit hyperactivity disorder-like phenotype by a complex chromosomal rearrangement. [provided by RefSeq, Aug 2010]

DOCK3 Gene-Disease associations (from GenCC):

neurodevelopmental disorder with impaired intellectual development, hypotonia, and ataxia
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
syndromic intellectual disability
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

DOCK3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008375734).

BP6

Variant 3-51361872-A-T is Benign according to our data. Variant chr3-51361872-A-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 547977.

BS2

High Homozygotes in GnomAdExome4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DOCK3	NM_004947.5 link	c.5020A>T	p.Met1674Leu	missense_variant	Exon 48 of 53	ENST00000266037.10	NP_004938.1	Q8IZD9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DOCK3	ENST00000266037.10 link	c.5020A>T	p.Met1674Leu	missense_variant	Exon 48 of 53	1	NM_004947.5	ENSP00000266037.8		Q8IZD9

Frequencies

GnomAD3 genomes

AF:

0.00127

AC:

193

AN:

152118

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000290

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00295

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.000283

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00185

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.00126

AC:

309

AN:

246018

AF XY:

0.00147

show subpopulations

Gnomad AFR exome

AF:

0.000195

Gnomad AMR exome

AF:

0.00114

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000373

Gnomad NFE exome

AF:

0.00174

Gnomad OTH exome

AF:

0.00117

GnomAD4 exome

AF:

0.00147

AC:

2152

AN:

1460868

Hom.:

Cov.:

AF XY:

0.00150

AC XY:

1089

AN XY:

726684

show subpopulations

African (AFR)

AF:

0.000239

AC:

AN:

33472

American (AMR)

AF:

0.000896

AC:

AN:

44654

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26090

East Asian (EAS)

AF:

0.00

AC:

AN:

39678

South Asian (SAS)

AF:

0.00200

AC:

172

AN:

86002

European-Finnish (FIN)

AF:

0.000562

AC:

AN:

53366

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.00161

AC:

1788

AN:

1111500

Other (OTH)

AF:

0.00184

AC:

111

AN:

60348

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

125

250

374

499

624

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

140

210

280

350

<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:

0.00127

AC:

193

AN:

152236

Hom.:

Cov.:

AF XY:

0.00132

AC XY:

AN XY:

74442

show subpopulations

African (AFR)

AF:

0.000289

AC:

AN:

41544

American (AMR)

AF:

0.00294

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.00124

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.000283

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00185

AC:

126

AN:

68002

Other (OTH)

AF:

0.000473

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00162

Hom.:

Bravo

AF:

0.00108

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00165

AC:

ExAC

AF:

0.00128

AC:

155

EpiCase

AF:

0.00224

EpiControl

AF:

0.00154

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:1

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 30, 2017

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

DOCK3: PM3, PM2:Supporting, BP4 -

Neurodevelopmental disorder with impaired intellectual development, hypotonia, and ataxia

Pathogenic:1

Aug 13, 2020

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.61

CADD

Benign

(source)

DANN

Benign

0.69

DEOGEN2

Benign

0.091

Eigen

Benign

-0.20

Eigen_PC

Benign

0.022

FATHMM_MKL

Uncertain

0.85

LIST_S2

Uncertain

0.88

M_CAP

Benign

0.0013

MetaRNN

Benign

0.0084

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.055

PhyloP100

3.2

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-0.47

REVEL

Benign

0.076

Sift

Benign

1.0

Sift4G

Benign

0.52

Polyphen

0.0

Vest4

0.15

MutPred

0.22

Loss of MoRF binding (P = 0.0723);

MVP

0.21

MPC

0.45

ClinPred

0.034

GERP RS

5.3

Varity_R

0.38

gMVP

0.076

Mutation Taster

=34/66

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over