rs143701798

Positions:

chr1-62663044-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.125A>G(p.Asn42Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000234 in 1,613,560 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0012 ( 2 hom., cov: 32)

Exomes 𝑓: 0.00013 ( 0 hom. )

Consequence

DOCK7
NM_001367561.1 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.0510

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=0.0067307055).

BP6

Variant 1-62663044-T-C is Benign according to our data. Variant chr1-62663044-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 475123.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00125 (190/152236) while in subpopulation AFR AF= 0.0039 (162/41544). AF 95% confidence interval is 0.00341. There are 2 homozygotes in gnomad4. There are 81 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DOCK7	NM_001367561.1 linkuse as main transcript	c.125A>G	p.Asn42Ser	missense_variant	2/50	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.125A>G	p.Asn42Ser	missense_variant	2/50	5	NM_001367561.1	ENSP00000489124.1		Q96N67-1

Frequencies

GnomAD3 genomes

AF:

0.00124

AC:

189

AN:

152116

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00389

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00192

GnomAD3 exomes

AF:

0.000314

AC:

AN:

251338

Hom.:

AF XY:

0.000265

AC XY:

AN XY:

135840

show subpopulations

Gnomad AFR exome

AF:

0.00357

Gnomad AMR exome

AF:

0.000318

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000981

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000528

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000128

AC:

187

AN:

1461324

Hom.:

Cov.:

AF XY:

0.000114

AC XY:

AN XY:

726980

show subpopulations

Gnomad4 AFR exome

AF:

0.00362

Gnomad4 AMR exome

AF:

0.000403

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000234

Gnomad4 OTH exome

AF:

0.000315

GnomAD4 genome

AF:

0.00125

AC:

190

AN:

152236

Hom.:

Cov.:

AF XY:

0.00109

AC XY:

AN XY:

74438

show subpopulations

Gnomad4 AFR

AF:

0.00390

Gnomad4 AMR

AF:

0.00131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000416

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00190

Alfa

AF:

0.000248

Hom.:

Bravo

AF:

0.00145

ESP6500AA

AF:

0.00409

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000428

AC:

EpiCase

AF:

0.0000546

EpiControl

AF:

0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Developmental and epileptic encephalopathy, 23

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 07, 2021	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Feb 20, 2024

- -

DOCK7-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 11, 2022

This variant is classified as likely 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

0.062

BayesDel_addAF

Benign

-0.70

BayesDel_noAF

Benign

-0.78

CADD

Benign

5.9

DANN

Benign

0.42

DEOGEN2

Benign

0.062

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

Eigen

Benign

-0.85

Eigen_PC

Benign

-0.70

FATHMM_MKL

Benign

0.29

LIST_S2

Benign

0.84

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

M_CAP

Benign

0.0039

MetaRNN

Benign

0.0067

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

MetaSVM

Benign

-0.93

MutationAssessor

Benign

-0.28

N;N;N;N;N;N;N

PrimateAI

Benign

0.40

PROVEAN

Benign

0.23

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

REVEL

Benign

0.079

Sift

Benign

1.0

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

Sift4G

Benign

1.0

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

Polyphen

0.0

.;B;B;.;.;.;.

Vest4

0.10

MVP

0.19

MPC

0.31

ClinPred

0.0029

GERP RS

-2.3

Varity_R

0.040

gMVP

0.25

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