1-62555843-G-T

Position:

chr1-62555843-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate

The NM_001367561.1(DOCK7):c.2578C>A(p.Pro860Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000228 in 1,611,680 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 0.00015 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00024 ( 0 hom. )

Consequence

DOCK7
NM_001367561.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 6.57

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 1 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=0.20532084).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DOCK7	NM_001367561.1 linkuse as main transcript	c.2578C>A	p.Pro860Thr	missense_variant	21/50	ENST00000635253.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DOCK7	ENST00000635253.2 linkuse as main transcript	c.2578C>A	p.Pro860Thr	missense_variant	21/50	5	NM_001367561.1		Q96N67-1

Frequencies

GnomAD3 genomes

AF:

0.000151

AC:

AN:

152064

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000309

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000229

AC:

AN:

249186

Hom.:

AF XY:

0.000193

AC XY:

AN XY:

134660

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000140

Gnomad NFE exome

AF:

0.000460

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.000236

AC:

344

AN:

1459616

Hom.:

Cov.:

AF XY:

0.000237

AC XY:

172

AN XY:

725940

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000751

Gnomad4 NFE exome

AF:

0.000300

Gnomad4 OTH exome

AF:

0.000116

GnomAD4 genome

AF:

0.000151

AC:

AN:

152064

Hom.:

Cov.:

AF XY:

0.000135

AC XY:

AN XY:

74268

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000309

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000267

Hom.:

Bravo

AF:

0.000132

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000362

AC:

EpiCase

AF:

0.000382

EpiControl

AF:

0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Developmental and epileptic encephalopathy, 23

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Oct 05, 2022	This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 860 of the DOCK7 protein (p.Pro860Thr). This variant is present in population databases (rs150032045, gnomAD 0.05%). 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: 541905). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt DOCK7 protein function. 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. -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 04, 2022

The c.2578C>A (p.P860T) alteration is located in exon 21 (coding exon 21) of the DOCK7 gene. This alteration results from a C to A substitution at nucleotide position 2578, causing the proline (P) at amino acid position 860 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jul 01, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.23

CADD

Uncertain

DANN

Uncertain

0.98

Eigen

Uncertain

0.46

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.94

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

M_CAP

Benign

0.015

MetaRNN

Benign

0.21

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

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.1

L;L;L;L;L;L;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.66

PROVEAN

Uncertain

-3.4

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

REVEL

Benign

0.20

Sift

Benign

0.053

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

Sift4G

Benign

0.14

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

Polyphen

0.036

B;B;D;P;D;.;.

Vest4

0.66

MVP

0.52

MPC

0.45

ClinPred

0.13

GERP RS

5.5

Varity_R

0.43

gMVP

0.63

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