4-3463370-C-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBS1BS2

The NM_173660.5(DOK7):c.-6C>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0246 in 1,487,404 control chromosomes in the GnomAD database, including 527 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.018 ( 23 hom., cov: 31)

Exomes 𝑓: 0.025 ( 504 hom. )

Consequence

DOK7
NM_173660.5 5_prime_UTR

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 2.69

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: Benign. The variant received -18 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.25).

BP6

Variant 4-3463370-C-G is Benign according to our data. Variant chr4-3463370-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 193509.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0175 (2626/149922) while in subpopulation NFE AF = 0.0268 (1813/67748). AF 95% confidence interval is 0.0257. There are 23 homozygotes in GnomAd4. There are 1197 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 23 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DOK7	NM_173660.5 link	c.-6C>G		5_prime_UTR_variant	Exon 1 of 7	ENST00000340083.6	NP_775931.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DOK7	ENST00000340083.6 link	c.-6C>G		5_prime_UTR_variant	Exon 1 of 7	1	NM_173660.5	ENSP00000344432.5

Frequencies

GnomAD3 genomes

AF:

0.0175

AC:

2625

AN:

149822

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00534

Gnomad AMI

AF:

0.0254

Gnomad AMR

AF:

0.0219

Gnomad ASJ

AF:

0.0156

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00814

Gnomad FIN

AF:

0.0113

Gnomad MID

AF:

0.00987

Gnomad NFE

AF:

0.0268

Gnomad OTH

AF:

0.0179

GnomAD2 exomes

AF:

0.0149

AC:

1799

AN:

121120

AF XY:

0.0148

show subpopulations

Gnomad AFR exome

AF:

0.00288

Gnomad AMR exome

AF:

0.00915

Gnomad ASJ exome

AF:

0.0144

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0129

Gnomad NFE exome

AF:

0.0220

Gnomad OTH exome

AF:

0.0187

GnomAD4 exome

AF:

0.0253

AC:

33901

AN:

1337482

Hom.:

504

Cov.:

AF XY:

0.0250

AC XY:

16523

AN XY:

662094

show subpopulations

African (AFR)

AF:

0.00419

AC:

114

AN:

27188

American (AMR)

AF:

0.0109

AC:

272

AN:

24988

Ashkenazi Jewish (ASJ)

AF:

0.0160

AC:

351

AN:

21910

East Asian (EAS)

AF:

0.0000306

AC:

AN:

32648

South Asian (SAS)

AF:

0.00556

AC:

392

AN:

70496

European-Finnish (FIN)

AF:

0.0124

AC:

448

AN:

36084

Middle Eastern (MID)

AF:

0.0199

AC:

AN:

3862

European-Non Finnish (NFE)

AF:

0.0292

AC:

31059

AN:

1065012

Other (OTH)

AF:

0.0215

AC:

1187

AN:

55294

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

1794

3589

5383

7178

8972

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1236

2472

3708

4944

6180

<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:

0.0175

AC:

2626

AN:

149922

Hom.:

Cov.:

AF XY:

0.0164

AC XY:

1197

AN XY:

73052

show subpopulations

African (AFR)

AF:

0.00532

AC:

216

AN:

40586

American (AMR)

AF:

0.0220

AC:

326

AN:

14830

Ashkenazi Jewish (ASJ)

AF:

0.0156

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5032

South Asian (SAS)

AF:

0.00815

AC:

AN:

4784

European-Finnish (FIN)

AF:

0.0113

AC:

115

AN:

10196

Middle Eastern (MID)

AF:

0.0106

AC:

AN:

284

European-Non Finnish (NFE)

AF:

0.0268

AC:

1813

AN:

67748

Other (OTH)

AF:

0.0177

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

129

258

386

515

644

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

150

<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:

0.0195

Hom.:

Bravo

AF:

0.0176

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

May 11, 2016

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 24, 2017

Athena Diagnostics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 29, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

DOK7-related disorder

Benign:1

Feb 26, 2020

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.25

CADD

Benign

(source)

DANN

Benign

0.96

PhyloP100

2.7

PromoterAI

0.020

Neutral

(source)

Mutation Taster

=298/2

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