4-3493455-C-T

Position:

chr4-3493455-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_173660.5(DOK7):c.1469C>T(p.Ser490Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00192 in 1,609,980 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0026 ( 4 hom., cov: 35)

Exomes 𝑓: 0.0019 ( 25 hom. )

Consequence

DOK7
NM_173660.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 2.49

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=0.0022628307).

BP6

Variant 4-3493455-C-T is Benign according to our data. Variant chr4-3493455-C-T is described in ClinVar as [Benign]. Clinvar id is 262868.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00258 (393/152362) while in subpopulation EAS AF= 0.0284 (147/5180). AF 95% confidence interval is 0.0246. There are 4 homozygotes in gnomad4. There are 210 alleles in male gnomad4 subpopulation. Median coverage is 35. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DOK7	NM_173660.5 linkuse as main transcript	c.1469C>T	p.Ser490Leu	missense_variant	7/7	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.1469C>T	p.Ser490Leu	missense_variant	7/7	1	NM_173660.5	ENSP00000344432	P1	Q18PE1-1
DOK7	ENST00000643608.1 linkuse as main transcript	c.1037C>T	p.Ser346Leu	missense_variant	5/8			ENSP00000495701
DOK7	ENST00000515886.5 linkuse as main transcript	c.539C>T	p.Ser180Leu	missense_variant	4/4	2		ENSP00000492194
DOK7	ENST00000507039.5 linkuse as main transcript	c.*690C>T		3_prime_UTR_variant	7/7	2		ENSP00000423614		Q18PE1-4

Frequencies

GnomAD3 genomes

AF:

0.00257

AC:

392

AN:

152244

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000410

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00288

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0285

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.0124

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000603

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.00528

AC:

1242

AN:

235078

Hom.:

AF XY:

0.00473

AC XY:

612

AN XY:

129510

show subpopulations

Gnomad AFR exome

AF:

0.000864

Gnomad AMR exome

AF:

0.00470

Gnomad ASJ exome

AF:

0.000104

Gnomad EAS exome

AF:

0.0363

Gnomad SAS exome

AF:

0.000635

Gnomad FIN exome

AF:

0.0135

Gnomad NFE exome

AF:

0.000970

Gnomad OTH exome

AF:

0.00430

GnomAD4 exome

AF:

0.00185

AC:

2699

AN:

1457618

Hom.:

Cov.:

AF XY:

0.00176

AC XY:

1275

AN XY:

724860

show subpopulations

Gnomad4 AFR exome

AF:

0.000299

Gnomad4 AMR exome

AF:

0.00438

Gnomad4 ASJ exome

AF:

0.0000768

Gnomad4 EAS exome

AF:

0.0270

Gnomad4 SAS exome

AF:

0.000816

Gnomad4 FIN exome

AF:

0.0144

Gnomad4 NFE exome

AF:

0.000420

Gnomad4 OTH exome

AF:

0.00233

GnomAD4 genome

AF:

0.00258

AC:

393

AN:

152362

Hom.:

Cov.:

AF XY:

0.00282

AC XY:

210

AN XY:

74504

show subpopulations

Gnomad4 AFR

AF:

0.000433

Gnomad4 AMR

AF:

0.00294

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0284

Gnomad4 SAS

AF:

0.00124

Gnomad4 FIN

AF:

0.0124

Gnomad4 NFE

AF:

0.000603

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.00214

Hom.:

Bravo

AF:

0.00240

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000499

AC:

ExAC

AF:

0.00474

AC:

569

Asia WGS

AF:

0.00808

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

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 3

Benign:1

Benign, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Sep 26, 2018

This variant was classified as: Benign. The following ACMG criteria were applied in classifying this variant: BS1,BS2. -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 14, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.46

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Benign

0.10

T;.;.

Eigen

Benign

-0.92

Eigen_PC

Benign

-0.89

FATHMM_MKL

Benign

0.26

LIST_S2

Benign

0.74

T;T;T

MetaRNN

Benign

0.0023

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.3

L;.;.

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Uncertain

0.68

PROVEAN

Benign

-2.1

N;.;.

REVEL

Benign

0.049

Sift

Benign

0.22

T;.;.

Sift4G

Benign

0.096

T;.;.

Polyphen

0.0010

B;.;.

Vest4

0.18

MVP

0.54

MPC

0.0048

ClinPred

0.0041

GERP RS

1.0

Varity_R

0.064

gMVP

0.13

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