chr4-3473439-C-T

Position:

chr4-3473439-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBS1BS2

The NM_173660.5(DOK7):c.134C>T(p.Ser45Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0054 in 1,611,020 control chromosomes in the GnomAD database, including 60 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0046 ( 1 hom., cov: 34)

Exomes 𝑓: 0.0055 ( 59 hom. )

Consequence

DOK7
NM_173660.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 0.707

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 PH (size 105) in uniprot entity DOK7_HUMAN there are 13 pathogenic changes around while only 3 benign (81%) in NM_173660.5

BP4

Computational evidence support a benign effect (MetaRNN=0.0065547824).

BP6

Variant 4-3473439-C-T is Benign according to our data. Variant chr4-3473439-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 196597.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-3473439-C-T is described in Lovd as [Pathogenic]. Variant chr4-3473439-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00464 (707/152344) while in subpopulation NFE AF= 0.00523 (356/68024). AF 95% confidence interval is 0.00478. There are 1 homozygotes in gnomad4. There are 326 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 59 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DOK7	NM_173660.5 linkuse as main transcript	c.134C>T	p.Ser45Leu	missense_variant	3/7	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.134C>T	p.Ser45Leu	missense_variant	3/7	1	NM_173660.5	ENSP00000344432	P1	Q18PE1-1

Frequencies

GnomAD3 genomes

AF:

0.00460

AC:

701

AN:

152226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00188

Gnomad AMI

AF:

0.0526

Gnomad AMR

AF:

0.000785

Gnomad ASJ

AF:

0.0461

Gnomad EAS

AF:

0.00308

Gnomad SAS

AF:

0.00289

Gnomad FIN

AF:

0.000753

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00523

Gnomad OTH

AF:

0.00430

GnomAD3 exomes

AF:

0.00550

AC:

1359

AN:

246904

Hom.:

AF XY:

0.00560

AC XY:

754

AN XY:

134588

show subpopulations

Gnomad AFR exome

AF:

0.00182

Gnomad AMR exome

AF:

0.00136

Gnomad ASJ exome

AF:

0.0488

Gnomad EAS exome

AF:

0.00190

Gnomad SAS exome

AF:

0.00454

Gnomad FIN exome

AF:

0.000789

Gnomad NFE exome

AF:

0.00513

Gnomad OTH exome

AF:

0.00598

GnomAD4 exome

AF:

0.00548

AC:

8000

AN:

1458676

Hom.:

Cov.:

AF XY:

0.00545

AC XY:

3958

AN XY:

725696

show subpopulations

Gnomad4 AFR exome

AF:

0.00168

Gnomad4 AMR exome

AF:

0.00132

Gnomad4 ASJ exome

AF:

0.0503

Gnomad4 EAS exome

AF:

0.00141

Gnomad4 SAS exome

AF:

0.00497

Gnomad4 FIN exome

AF:

0.00122

Gnomad4 NFE exome

AF:

0.00499

Gnomad4 OTH exome

AF:

0.00759

GnomAD4 genome

AF:

0.00464

AC:

707

AN:

152344

Hom.:

Cov.:

AF XY:

0.00438

AC XY:

326

AN XY:

74496

show subpopulations

Gnomad4 AFR

AF:

0.00200

Gnomad4 AMR

AF:

0.000784

Gnomad4 ASJ

AF:

0.0461

Gnomad4 EAS

AF:

0.00309

Gnomad4 SAS

AF:

0.00310

Gnomad4 FIN

AF:

0.000753

Gnomad4 NFE

AF:

0.00523

Gnomad4 OTH

AF:

0.00425

Alfa

AF:

0.00670

Hom.:

Bravo

AF:

0.00477

TwinsUK

AF:

0.00351

AC:

ALSPAC

AF:

0.00259

AC:

ESP6500AA

AF:

0.00308

AC:

ESP6500EA

AF:

0.00640

AC:

ExAC

AF:

0.00511

AC:

618

Asia WGS

AF:

0.00318

AC:

AN:

3478

EpiCase

AF:

0.00529

EpiControl

AF:

0.00516

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 25, 2022	Variant summary: DOK7 c.134C>T (p.Ser45Leu) results in a non-conservative amino acid change located in the Pleckstrin homology domain (IPR001849) of the encoded protein sequence. Three of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0055 in 246904 control chromosomes in the gnomAD database, including 19 homozygotes. The observed variant frequency is approximately 4 fold of the estimated maximal expected allele frequency for a pathogenic variant in DOK7 causing Congenital Myasthenic Syndrome phenotype (0.0014), strongly suggesting that the variant is benign. c.134C>T has been reported in the literature in the heterozygous state together with the pathogenic variant c.1124_1127dupTGCC in individuals affected with Congenital Myasthenic Syndrome (example, Muller_2007, Ben Ammar_2010, Lorenzoni_2013). However, these reports do not provide unequivocal conclusions about association of the variant with Congenital Myasthenic Syndrome. At least one publication reports experimental evidence which suggests the variant has little to no impact on protein function (Cossins_2012). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Two laboratories have classified the variant as benign, three as likely benign, and one as VUS. Based on the evidence outlined above, the variant was classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 02, 2018	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided

Benign:4

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	DOK7: BP4, BS2 -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Apr 13, 2015	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 14, 2021	This variant is associated with the following publications: (PMID: 22661499, 23657916, 23452772, 20562457, 20012313, 26754003, 17439981, 31044425) -

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

- -

Fetal akinesia deformation sequence 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Mendelics

Aug 22, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.096

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.36

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.43

.;T

Eigen

Benign

-0.60

Eigen_PC

Benign

-0.63

FATHMM_MKL

Benign

0.26

LIST_S2

Uncertain

0.87

D;D

M_CAP

Benign

0.062

MetaRNN

Benign

0.0066

T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

1.5

L;L

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Uncertain

0.50

PROVEAN

Uncertain

-3.6

D;D

REVEL

Benign

0.17

Sift

Benign

0.67

T;T

Sift4G

Uncertain

0.042

D;T

Polyphen

0.38

.;B

Vest4

0.54

MVP

0.78

MPC

0.0054

ClinPred

0.030

GERP RS

2.8

Varity_R

0.12

gMVP

0.23

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