chr4-3493077-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_173660.5(DOK7):​c.1091G>T​(p.Arg364Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000211 in 1,423,768 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R364Q) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 34)
Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

DOK7
NM_173660.5 missense

Scores

4
15

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.93

Publications

0 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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.20320961).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
DOK7NM_173660.5 linkc.1091G>T p.Arg364Leu missense_variant Exon 7 of 7 ENST00000340083.6 NP_775931.3 Q18PE1-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
DOK7ENST00000340083.6 linkc.1091G>T p.Arg364Leu missense_variant Exon 7 of 7 1 NM_173660.5 ENSP00000344432.5 Q18PE1-1

Frequencies

GnomAD3 genomes
Cov.:
34
GnomAD4 exome
AF:
0.00000211
AC:
3
AN:
1423768
Hom.:
0
Cov.:
111
AF XY:
0.00000142
AC XY:
1
AN XY:
706098
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
32918
American (AMR)
AF:
0.00
AC:
0
AN:
40096
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25550
East Asian (EAS)
AF:
0.0000528
AC:
2
AN:
37852
South Asian (SAS)
AF:
0.00
AC:
0
AN:
82482
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
42572
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5730
European-Non Finnish (NFE)
AF:
9.11e-7
AC:
1
AN:
1097408
Other (OTH)
AF:
0.00
AC:
0
AN:
59160
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.492
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
Cov.:
34

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Fetal akinesia deformation sequence 1;C1850792:Congenital myasthenic syndrome 10 Uncertain:1
Aug 11, 2021
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change replaces arginine with leucine at codon 364 of the DOK7 protein (p.Arg364Leu). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and leucine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with DOK7-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.10
BayesDel_addAF
Benign
-0.10
T
BayesDel_noAF
Benign
-0.39
CADD
Benign
14
DANN
Uncertain
0.99
DEOGEN2
Benign
0.40
T;.;.
Eigen
Benign
-0.26
Eigen_PC
Benign
-0.34
FATHMM_MKL
Benign
0.39
N
LIST_S2
Benign
0.76
T;T;T
M_CAP
Benign
0.076
D
MetaRNN
Benign
0.20
T;T;T
MetaSVM
Benign
-0.86
T
MutationAssessor
Uncertain
2.1
M;.;.
PhyloP100
1.9
PrimateAI
Uncertain
0.72
T
PROVEAN
Uncertain
-3.7
D;.;.
REVEL
Benign
0.062
Sift
Benign
0.22
T;.;.
Sift4G
Benign
0.10
T;.;.
Polyphen
0.029
B;.;.
Vest4
0.34
MutPred
0.32
Gain of helix (P = 0.0425);.;.;
MVP
0.76
MPC
0.0049
ClinPred
0.72
D
GERP RS
-0.41
Varity_R
0.18
gMVP
0.12
Mutation Taster
=88/12
polymorphism

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

Other links and lift over

dbSNP: rs201304841; hg19: chr4-3494804; API