rs746518826

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP2BP4

The NM_001367561.1(DOCK7):c.4480G>A(p.Val1494Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000162 in 1,607,250 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

DOCK7
NM_001367561.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 7.91

Variant links:

Genes affected

DOCK7 (HGNC:19190): (dedicator of cytokinesis 7) The protein encoded by this gene is a guanine nucleotide exchange factor (GEF) that plays a role in axon formation and neuronal polarization. The encoded protein displays GEF activity toward RAC1 and RAC3 Rho small GTPases but not toward CDC42. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2012]

DOCK7 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant where missense usually causes diseases, DOCK7

BP4

Computational evidence support a benign effect (MetaRNN=0.36937267).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DOCK7	NM_001367561.1 linkuse as main transcript	c.4480G>A	p.Val1494Ile	missense_variant	36/50	ENST00000635253.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DOCK7	ENST00000635253.2 linkuse as main transcript	c.4480G>A	p.Val1494Ile	missense_variant	36/50	5	NM_001367561.1		Q96N67-1

Frequencies

GnomAD3 genomes

AF:

0.0000527

AC:

AN:

151900

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000967

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000203

AC:

AN:

246136

Hom.:

AF XY:

0.0000225

AC XY:

AN XY:

133232

show subpopulations

Gnomad AFR exome

AF:

0.000124

Gnomad AMR exome

AF:

0.0000302

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000178

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000117

AC:

AN:

1455232

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

724180

show subpopulations

Gnomad4 AFR exome

AF:

0.000182

Gnomad4 AMR exome

AF:

0.0000465

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000721

Gnomad4 OTH exome

AF:

0.0000167

GnomAD4 genome

AF:

0.0000592

AC:

AN:

152018

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74288

show subpopulations

Gnomad4 AFR

AF:

0.000121

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.0000659

Hom.:

Bravo

AF:

0.000121

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 22, 2023

The c.4387G>A (p.V1463I) alteration is located in exon 35 (coding exon 35) of the DOCK7 gene. This alteration results from a G to A substitution at nucleotide position 4387, causing the valine (V) at amino acid position 1463 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Developmental and epileptic encephalopathy, 23

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 01, 2022

This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 1485 of the DOCK7 protein (p.Val1485Ile). This variant is present in population databases (rs746518826, gnomAD 0.008%). This variant has not been reported in the literature in individuals affected with DOCK7-related conditions. ClinVar contains an entry for this variant (Variation ID: 573337). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Feb 03, 2022

BP4, PM2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.26

Cadd

Pathogenic

Dann

Uncertain

1.0

Eigen

Uncertain

0.66

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.91

D;D;D;D;D;D;D

M_CAP

Benign

0.027

MetaRNN

Benign

0.37

T;T;T;T;T;T;T

MetaSVM

Benign

-0.58

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-0.73

N;.;N;.;.;.;.

REVEL

Benign

0.17

Sift

Benign

0.13

T;.;T;.;.;.;.

Sift4G

Benign

0.10

T;T;T;.;T;T;T

Polyphen

0.99

D;D;D;.;D;D;D

Vest4

0.35

MVP

0.54

MPC

0.35

ClinPred

0.38

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.20

gMVP

0.22

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over