rs16844464

Positions:

chr4-3493229-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_173660.5(DOK7):c.1243C>T(p.Pro415Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0414 in 1,611,910 control chromosomes in the GnomAD database, including 1,980 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P415R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.062 ( 461 hom., cov: 34)

Exomes 𝑓: 0.039 ( 1519 hom. )

Consequence

DOK7
NM_173660.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.413

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0017016828).

BP6

Variant 4-3493229-C-T is Benign according to our data. Variant chr4-3493229-C-T is described in ClinVar as [Benign]. Clinvar id is 128908.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-3493229-C-T is described in Lovd as [Benign]. Variant chr4-3493229-C-T is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.12 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DOK7	NM_173660.5 linkuse as main transcript	c.1243C>T	p.Pro415Ser	missense_variant	7/7	ENST00000340083.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DOK7	ENST00000340083.6 linkuse as main transcript	c.1243C>T	p.Pro415Ser	missense_variant	7/7	1	NM_173660.5	P1	Q18PE1-1
DOK7	ENST00000643608.1 linkuse as main transcript	c.811C>T	p.Pro271Ser	missense_variant	5/8
DOK7	ENST00000515886.5 linkuse as main transcript	c.313C>T	p.Pro105Ser	missense_variant	4/4	2
DOK7	ENST00000507039.5 linkuse as main transcript	c.*464C>T		3_prime_UTR_variant	7/7	2			Q18PE1-4

Frequencies

GnomAD3 genomes

AF:

0.0622

AC:

9464

AN:

152194

Hom.:

452

Cov.:

show subpopulations

Gnomad AFR

AF:

0.123

Gnomad AMI

AF:

0.0811

Gnomad AMR

AF:

0.0715

Gnomad ASJ

AF:

0.0317

Gnomad EAS

AF:

0.0393

Gnomad SAS

AF:

0.0621

Gnomad FIN

AF:

0.0165

Gnomad MID

AF:

0.0538

Gnomad NFE

AF:

0.0341

Gnomad OTH

AF:

0.0454

GnomAD3 exomes

AF:

0.0533

AC:

12757

AN:

239344

Hom.:

536

AF XY:

0.0506

AC XY:

6636

AN XY:

131240

show subpopulations

Gnomad AFR exome

AF:

0.123

Gnomad AMR exome

AF:

0.107

Gnomad ASJ exome

AF:

0.0328

Gnomad EAS exome

AF:

0.0417

Gnomad SAS exome

AF:

0.0599

Gnomad FIN exome

AF:

0.0136

Gnomad NFE exome

AF:

0.0358

Gnomad OTH exome

AF:

0.0537

GnomAD4 exome

AF:

0.0393

AC:

57303

AN:

1459598

Hom.:

1519

Cov.:

AF XY:

0.0396

AC XY:

28742

AN XY:

726088

show subpopulations

Gnomad4 AFR exome

AF:

0.113

Gnomad4 AMR exome

AF:

0.102

Gnomad4 ASJ exome

AF:

0.0300

Gnomad4 EAS exome

AF:

0.0256

Gnomad4 SAS exome

AF:

0.0616

Gnomad4 FIN exome

AF:

0.0166

Gnomad4 NFE exome

AF:

0.0340

Gnomad4 OTH exome

AF:

0.0455

GnomAD4 genome

AF:

0.0623

AC:

9495

AN:

152312

Hom.:

461

Cov.:

AF XY:

0.0612

AC XY:

4557

AN XY:

74474

show subpopulations

Gnomad4 AFR

AF:

0.122

Gnomad4 AMR

AF:

0.0720

Gnomad4 ASJ

AF:

0.0317

Gnomad4 EAS

AF:

0.0396

Gnomad4 SAS

AF:

0.0607

Gnomad4 FIN

AF:

0.0165

Gnomad4 NFE

AF:

0.0341

Gnomad4 OTH

AF:

0.0534

Alfa

AF:

0.0421

Hom.:

232

Bravo

AF:

0.0689

TwinsUK

AF:

0.0324

AC:

120

ALSPAC

AF:

0.0332

AC:

128

ESP6500AA

AF:

0.122

AC:

533

ESP6500EA

AF:

0.0336

AC:

288

ExAC

AF:

0.0525

AC:

6335

Asia WGS

AF:

0.0850

AC:

293

AN:

3478

EpiCase

AF:

0.0348

EpiControl

AF:

0.0376

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 08, 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, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 11, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Feb 15, 2016	- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.45

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.36

T;.;.

Eigen

Benign

-0.61

Eigen_PC

Benign

-0.78

FATHMM_MKL

Benign

0.10

LIST_S2

Benign

0.68

T;T;T

MetaRNN

Benign

0.0017

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.0

M;.;.

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Uncertain

0.51

PROVEAN

Uncertain

-3.9

D;.;.

REVEL

Benign

0.073

Sift

Uncertain

0.016

D;.;.

Sift4G

Benign

0.19

T;.;.

Polyphen

0.0070

B;.;.

Vest4

0.0090

MPC

0.0045

ClinPred

0.011

GERP RS

1.0

Varity_R

0.17

gMVP

0.11

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