rs72913293

Positions:

chr1-62619959-T-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_001367561.1(DOCK7):c.1460A>G(p.Lys487Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00387 in 1,613,714 control chromosomes in the GnomAD database, including 60 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.010 ( 22 hom., cov: 31)

Exomes 𝑓: 0.0032 ( 38 hom. )

Consequence

DOCK7
NM_001367561.1 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 7.62

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 Benign. Variant got -19 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), DOCK7. . Gene score misZ 3.4194 (greater than the threshold 3.09). Trascript score misZ 3.8677 (greater than threshold 3.09). GenCC has associacion of gene with developmental and epileptic encephalopathy, 23, developmental and epileptic encephalopathy.

BP4

Computational evidence support a benign effect (MetaRNN=0.008763492).

BP6

Variant 1-62619959-T-C is Benign according to our data. Variant chr1-62619959-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 218580.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-62619959-T-C is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0103 (1566/152242) while in subpopulation AFR AF= 0.028 (1162/41530). AF 95% confidence interval is 0.0266. There are 22 homozygotes in gnomad4. There are 782 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 22 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DOCK7	NM_001367561.1 linkuse as main transcript	c.1460A>G	p.Lys487Arg	missense_variant	13/50	ENST00000635253.2	NP_001354490.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DOCK7	ENST00000635253.2 linkuse as main transcript	c.1460A>G	p.Lys487Arg	missense_variant	13/50	5	NM_001367561.1	ENSP00000489124		Q96N67-1

Frequencies

GnomAD3 genomes

AF:

0.0103

AC:

1562

AN:

152124

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0280

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00641

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00707

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00309

Gnomad OTH

AF:

0.00766

GnomAD3 exomes

AF:

0.00463

AC:

1163

AN:

251150

Hom.:

AF XY:

0.00405

AC XY:

550

AN XY:

135758

show subpopulations

Gnomad AFR exome

AF:

0.0291

Gnomad AMR exome

AF:

0.00215

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000785

Gnomad FIN exome

AF:

0.00647

Gnomad NFE exome

AF:

0.00378

Gnomad OTH exome

AF:

0.00375

GnomAD4 exome

AF:

0.00320

AC:

4677

AN:

1461472

Hom.:

Cov.:

AF XY:

0.00304

AC XY:

2207

AN XY:

727044

show subpopulations

Gnomad4 AFR exome

AF:

0.0309

Gnomad4 AMR exome

AF:

0.00244

Gnomad4 ASJ exome

AF:

0.0000766

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000963

Gnomad4 FIN exome

AF:

0.00661

Gnomad4 NFE exome

AF:

0.00263

Gnomad4 OTH exome

AF:

0.00277

GnomAD4 genome

AF:

0.0103

AC:

1566

AN:

152242

Hom.:

Cov.:

AF XY:

0.0105

AC XY:

782

AN XY:

74458

show subpopulations

Gnomad4 AFR

AF:

0.0280

Gnomad4 AMR

AF:

0.00641

Gnomad4 ASJ

AF:

0.000576

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.00707

Gnomad4 NFE

AF:

0.00309

Gnomad4 OTH

AF:

0.00758

Alfa

AF:

0.00403

Hom.:

Bravo

AF:

0.0109

TwinsUK

AF:

0.00297

AC:

ALSPAC

AF:

0.00234

AC:

ESP6500AA

AF:

0.0306

AC:

135

ESP6500EA

AF:

0.00349

AC:

ExAC

AF:

0.00577

AC:

700

Asia WGS

AF:

0.00231

AC:

AN:

3478

EpiCase

AF:

0.00164

EpiControl

AF:

0.00243

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 08, 2023	See Variant Classification Assertion Criteria. -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Dec 21, 2015	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Apr 14, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 08, 2019	- -

Developmental and epileptic encephalopathy, 23

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

DOCK7-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 17, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.34

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.62

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

Eigen

Uncertain

0.68

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.99

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

MetaRNN

Benign

0.0088

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

MetaSVM

Benign

-0.83

MutationAssessor

Uncertain

2.4

M;M;M;M;M;M;M

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.69

PROVEAN

Uncertain

-2.4

N;.;N;.;.;.;D

REVEL

Benign

0.20

Sift

Benign

0.069

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

Sift4G

Uncertain

0.0040

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

Polyphen

1.0, 0.97, 0.99, 1.0

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

Vest4

0.76

MVP

0.69

MPC

0.60

ClinPred

0.033

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.36

gMVP

0.83

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