chr4-3485595-G-A

Position:

chr4-3485595-G-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBA1

The NM_173660.5(DOK7):c.589G>A(p.Asp197Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00426 in 1,607,942 control chromosomes in the GnomAD database, including 228 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.022 ( 113 hom., cov: 34)

Exomes 𝑓: 0.0024 ( 115 hom. )

Consequence

DOK7
NM_173660.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 9.24

Variant links:

Genes affected

DOK7 (HGNC:26594): (docking protein 7) The protein encoded by this gene is essential for neuromuscular synaptogenesis. The protein functions in aneural activation of muscle-specific receptor kinase, which is required for postsynaptic differentiation, and in the subsequent clustering of the acetylcholine receptor in myotubes. This protein can also induce autophosphorylation of muscle-specific receptor kinase. Mutations in this gene are a cause of familial limb-girdle myasthenia autosomal recessive, which is also known as congenital myasthenic syndrome type 1B. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2009]

DOK7 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

PM1

In a domain IRS-type PTB (size 105) in uniprot entity DOK7_HUMAN there are 29 pathogenic changes around while only 0 benign (100%) in NM_173660.5

BP4

Computational evidence support a benign effect (MetaRNN=0.005733669).

BP6

Variant 4-3485595-G-A is Benign according to our data. Variant chr4-3485595-G-A is described in ClinVar as [Benign]. Clinvar id is 128913.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-3485595-G-A is described in Lovd as [Benign]. Variant chr4-3485595-G-A is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0722 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DOK7	NM_173660.5 linkuse as main transcript	c.589G>A	p.Asp197Asn	missense_variant	5/7	ENST00000340083.6	NP_775931.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DOK7	ENST00000340083.6 linkuse as main transcript	c.589G>A	p.Asp197Asn	missense_variant	5/7	1	NM_173660.5	ENSP00000344432	P1	Q18PE1-1

Frequencies

GnomAD3 genomes

AF:

0.0218

AC:

3324

AN:

152168

Hom.:

113

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0744

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0101

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000661

Gnomad OTH

AF:

0.0202

GnomAD3 exomes

AF:

0.00579

AC:

1423

AN:

245954

Hom.:

AF XY:

0.00460

AC XY:

614

AN XY:

133408

show subpopulations

Gnomad AFR exome

AF:

0.0735

Gnomad AMR exome

AF:

0.00545

Gnomad ASJ exome

AF:

0.000101

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000234

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000449

Gnomad OTH exome

AF:

0.00370

GnomAD4 exome

AF:

0.00242

AC:

3516

AN:

1455656

Hom.:

115

Cov.:

AF XY:

0.00217

AC XY:

1568

AN XY:

724046

show subpopulations

Gnomad4 AFR exome

AF:

0.0755

Gnomad4 AMR exome

AF:

0.00604

Gnomad4 ASJ exome

AF:

0.000154

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000199

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000331

Gnomad4 OTH exome

AF:

0.00551

GnomAD4 genome

AF:

0.0219

AC:

3333

AN:

152286

Hom.:

113

Cov.:

AF XY:

0.0212

AC XY:

1580

AN XY:

74452

show subpopulations

Gnomad4 AFR

AF:

0.0744

Gnomad4 AMR

AF:

0.0101

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000662

Gnomad4 OTH

AF:

0.0199

Alfa

AF:

0.0114

Hom.:

Bravo

AF:

0.0243

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.0645

AC:

284

ESP6500EA

AF:

0.000581

AC:

ExAC

AF:

0.00726

AC:

881

Asia WGS

AF:

0.00375

AC:

AN:

3478

EpiCase

AF:

0.000660

EpiControl

AF:

0.000900

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 31, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 06, 2017	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Fetal akinesia deformation sequence 1;C1850792:Congenital myasthenic syndrome 10

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.72

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.20

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.26

T;.

Eigen

Uncertain

0.33

Eigen_PC

Uncertain

0.39

FATHMM_MKL

Uncertain

0.90

LIST_S2

Pathogenic

0.98

D;D

MetaRNN

Benign

0.0057

T;T

MetaSVM

Benign

-0.73

MutationTaster

Benign

1.0

D;D;N

PrimateAI

Pathogenic

0.80

PROVEAN

Uncertain

-3.3

D;.

REVEL

Uncertain

0.41

Sift

Benign

0.037

D;.

Sift4G

Uncertain

0.011

D;.

Polyphen

1.0

D;.

Vest4

0.71

MVP

0.86

MPC

0.020

ClinPred

0.032

GERP RS

3.8

Varity_R

0.59

gMVP

0.70

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