4-3493157-G-A

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.1171G>A(p.Gly391Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00104 in 1,605,702 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G391E) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00074 ( 1 hom., cov: 34)

Exomes 𝑓: 0.0011 ( 1 hom. )

Consequence

DOK7
NM_173660.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:1

Conservation

PhyloP100: 1.77

Publications

5 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=0.013844073).

BP6

Variant 4-3493157-G-A is Benign according to our data. Variant chr4-3493157-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 465670.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DOK7	NM_173660.5 link	c.1171G>A	p.Gly391Arg	missense_variant	Exon 7 of 7	ENST00000340083.6	NP_775931.3	Q18PE1-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
DOK7	ENST00000340083.6 link	c.1171G>A	p.Gly391Arg	missense_variant	Exon 7 of 7	1	NM_173660.5	ENSP00000344432.5	Q18PE1-1
DOK7	ENST00000643608.1 link	c.739G>A	p.Gly247Arg	missense_variant	Exon 5 of 8			ENSP00000495701.1	A0A2R8Y701
DOK7	ENST00000515886.5 link	c.241G>A	p.Gly81Arg	missense_variant	Exon 4 of 4	2		ENSP00000492194.1	A0A1W2PRA3
DOK7	ENST00000507039.5 link	c.*392G>A		3_prime_UTR_variant	Exon 7 of 7	2		ENSP00000423614.1	Q18PE1-4

Frequencies

GnomAD3 genomes

AF:

0.000736

AC:

112

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000290

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00131

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00101

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.000847

AC:

193

AN:

227988

AF XY:

0.000880

show subpopulations

Gnomad AFR exome

AF:

0.000219

Gnomad AMR exome

AF:

0.00123

Gnomad ASJ exome

AF:

0.00105

Gnomad EAS exome

AF:

0.0000585

Gnomad FIN exome

AF:

0.0000537

Gnomad NFE exome

AF:

0.00125

Gnomad OTH exome

AF:

0.00195

GnomAD4 exome

AF:

0.00107

AC:

1557

AN:

1453386

Hom.:

Cov.:

114

AF XY:

0.00102

AC XY:

738

AN XY:

722634

show subpopulations

African (AFR)

AF:

0.000270

AC:

AN:

33314

American (AMR)

AF:

0.00130

AC:

AN:

44008

Ashkenazi Jewish (ASJ)

AF:

0.00189

AC:

AN:

25962

East Asian (EAS)

AF:

0.00

AC:

AN:

39248

South Asian (SAS)

AF:

0.0000586

AC:

AN:

85322

European-Finnish (FIN)

AF:

0.000119

AC:

AN:

50276

Middle Eastern (MID)

AF:

0.000521

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00123

AC:

1364

AN:

1109468

Other (OTH)

AF:

0.00107

AC:

AN:

60026

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

119

238

358

477

596

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

144

192

240

<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:

0.000735

AC:

112

AN:

152316

Hom.:

Cov.:

AF XY:

0.000631

AC XY:

AN XY:

74486

show subpopulations

African (AFR)

AF:

0.000289

AC:

AN:

41558

American (AMR)

AF:

0.00131

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00115

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5178

South Asian (SAS)

AF:

0.000414

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0000941

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00101

AC:

AN:

68024

Other (OTH)

AF:

0.00142

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.520

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:

0.00102

Hom.:

Bravo

AF:

0.000892

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.000228

AC:

ESP6500EA

AF:

0.00117

AC:

ExAC

AF:

0.000739

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Nov 11, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

De novo variant with confirmed parentage in a patient in published literature from a cohort of individuals with developmental disorders; however, detailed clinical information was not provided, and the patient harbored additional de novo variants (PMID: 33057194); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 35982159, 33057194) -

Sep 01, 2021

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 30, 2023

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Uncertain:1

Apr 14, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1171G>A (p.G391R) alteration is located in exon 7 (coding exon 7) of the DOK7 gene. This alteration results from a G to A substitution at nucleotide position 1171, causing the glycine (G) at amino acid position 391 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Congenital myasthenic syndrome 10

Uncertain:1

Jun 01, 2017

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Benign:1

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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

0.13

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.35

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.11

T;.;.

Eigen

Benign

-0.092

Eigen_PC

Benign

-0.28

FATHMM_MKL

Benign

0.081

LIST_S2

Benign

0.80

T;D;D

M_CAP

Uncertain

0.19

MetaRNN

Benign

0.014

T;T;T

MetaSVM

Benign

-0.81

MutationAssessor

Uncertain

2.3

M;.;.

PhyloP100

1.8

PrimateAI

Uncertain

0.62

PROVEAN

Uncertain

-2.5

D;.;.

REVEL

Benign

0.19

Sift

Benign

0.041

D;.;.

Sift4G

Uncertain

0.044

D;.;.

Polyphen

0.94

P;.;.

Vest4

0.18

MutPred

0.49

Gain of solvent accessibility (P = 0.0014);.;.;

MVP

0.79

MPC

0.0082

ClinPred

0.024

GERP RS

2.8

Varity_R

0.092

gMVP

0.36

Mutation Taster

=88/12

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