4-3493332-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_173660.5(DOK7):c.1346C>T(p.Thr449Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000831 in 1,601,106 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T449T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000079 ( 0 hom. )

Consequence

DOK7
NM_173660.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 0.137

Publications

2 publications found

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 Gene-Disease associations (from GenCC):

congenital myasthenic syndrome 10
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), PanelApp Australia
fetal akinesia deformation sequence 3
Inheritance: AR Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
fetal akinesia deformation sequence 1
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
postsynaptic congenital myasthenic syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

DOK7 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.052502096).

BP6

Variant 4-3493332-C-T is Benign according to our data. Variant chr4-3493332-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 465676.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DOK7	NM_173660.5 link	c.1346C>T	p.Thr449Met	missense_variant	Exon 7 of 7	ENST00000340083.6	NP_775931.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
DOK7	ENST00000340083.6 link	c.1346C>T	p.Thr449Met	missense_variant	Exon 7 of 7	1	NM_173660.5	ENSP00000344432.5
DOK7	ENST00000643608.1 link	c.914C>T	p.Thr305Met	missense_variant	Exon 5 of 8			ENSP00000495701.1
DOK7	ENST00000515886.5 link	c.416C>T	p.Thr139Met	missense_variant	Exon 4 of 4	2		ENSP00000492194.1
DOK7	ENST00000507039.5 link	c.*567C>T		3_prime_UTR_variant	Exon 7 of 7	2		ENSP00000423614.1

Frequencies

GnomAD3 genomes

AF:

0.000125

AC:

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000290

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.000955

GnomAD2 exomes

AF:

0.000102

AC:

AN:

215368

AF XY:

0.000109

show subpopulations

Gnomad AFR exome

AF:

0.000331

Gnomad AMR exome

AF:

0.000155

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000606

Gnomad FIN exome

AF:

0.0000519

Gnomad NFE exome

AF:

0.000119

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000787

AC:

114

AN:

1448822

Hom.:

Cov.:

AF XY:

0.0000751

AC XY:

AN XY:

719430

show subpopulations

African (AFR)

AF:

0.000722

AC:

AN:

33238

American (AMR)

AF:

0.000161

AC:

AN:

43356

Ashkenazi Jewish (ASJ)

AF:

0.000389

AC:

AN:

25732

East Asian (EAS)

AF:

0.00

AC:

AN:

39184

South Asian (SAS)

AF:

0.0000236

AC:

AN:

84916

European-Finnish (FIN)

AF:

0.0000591

AC:

AN:

50780

Middle Eastern (MID)

AF:

0.000522

AC:

AN:

5746

European-Non Finnish (NFE)

AF:

0.0000506

AC:

AN:

1106108

Other (OTH)

AF:

0.000151

AC:

AN:

59762

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000125

AC:

AN:

152284

Hom.:

Cov.:

AF XY:

0.000107

AC XY:

AN XY:

74454

show subpopulations

African (AFR)

AF:

0.000289

AC:

AN:

41556

American (AMR)

AF:

0.0000654

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.000207

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68012

Other (OTH)

AF:

0.000945

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.000166

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000359

AC:

ExAC

AF:

0.000119

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

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

Uncertain:1

Oct 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 449 of the DOK7 protein (p.Thr449Met). This variant is present in population databases (rs373864257, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with DOK7-related conditions. ClinVar contains an entry for this variant (Variation ID: 465676). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt DOK7 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided

Benign:1

Dec 31, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.41

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.088

T;.;.

Eigen

Benign

-0.60

Eigen_PC

Benign

-0.70

FATHMM_MKL

Benign

0.084

LIST_S2

Benign

0.75

T;T;T

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.053

T;T;T

MetaSVM

Benign

-0.83

MutationAssessor

Benign

1.5

L;.;.

PhyloP100

0.14

PrimateAI

Uncertain

0.62

PROVEAN

Benign

-1.8

N;.;.

REVEL

Benign

0.055

Sift

Uncertain

0.012

D;.;.

Sift4G

Benign

0.095

T;.;.

Polyphen

0.047

B;.;.

Vest4

0.15

MVP

0.71

MPC

0.0074

ClinPred

0.015

GERP RS

2.1

Varity_R

0.059

gMVP

0.13

Mutation Taster

=98/2

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over