4-3463382-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PS1_Moderate PM2 BP4

The NM_173660.5(DOK7):c.7G>A(p.Glu3Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000737 in 1,493,466 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000074 (0 hom.)
• Consequence: DOK7 NM_173660.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.19

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PS1: Transcript NM_173660.5 (DOK7) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2752148).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DOK7	NM_173660.5	c.7G>A	p.Glu3Lys	missense_variant	1/7	ENST00000340083.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DOK7	ENST00000340083.6	c.7G>A	p.Glu3Lys	missense_variant	1/7	1	NM_173660.5	P1

Frequencies

GnomAD3 genomes AF: 0.00000662 AC: 1 AN: 151010 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000198

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000321 AC: 4 AN: 124800 Hom.: 0 AF XY: 0.0000141 AC XY: 1 AN XY: 71160

Gnomad AFR exome AF: 0.000189

Gnomad AMR exome AF: 0.0000625

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000321

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000745 AC: 10 AN: 1342348 Hom.: 0 Cov.: 33 AF XY: 0.00000451 AC XY: 3 AN XY: 664892

Gnomad4 AFR exome AF: 0.0000366

Gnomad4 AMR exome AF: 0.0000385

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000750

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000662 AC: 1 AN: 151118 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 73858

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000198

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ExAC AF: 0.0000176 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 30, 2021

This sequence change replaces glutamic acid with lysine at codon 3 of the DOK7 protein (p.Glu3Lys). The glutamic acid residue is weakly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs763233743, ExAC 0.01%). This missense change has been observed in individual(s) with clinical features of congenital myasthenic syndrome (PMID: 22661499; Invitae). 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. Experimental studies have shown that this missense change affects DOK7 function (PMID: 22661499). 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	Pathogenic	0.89
BayesDel_addAF	Uncertain	0.020	T
BayesDel_noAF	Uncertain	0.060
Cadd	Pathogenic	27
Dann	Uncertain	1.0
Eigen	Benign	0.0031
Eigen_PC	Benign	0.049
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.69	T;T;T
M_CAP	Pathogenic	0.92	D
MetaRNN	Benign	0.28	T;T;T
MetaSVM	Uncertain	-0.23	T
MutationAssessor	Benign	0.69	N;N;.
MutationTaster	Benign	0.86	N;N;N
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-1.3	N;N;.
REVEL	Uncertain	0.43
Sift	Uncertain	0.014	D;D;.
Sift4G	Uncertain	0.020	D;D;.
Polyphen		0.86	.;P;.
Vest4		0.36
MutPred		0.34		Gain of MoRF binding (P = 5e-04);Gain of MoRF binding (P = 5e-04);Gain of MoRF binding (P = 5e-04);
MVP		0.90
MPC		0.0055
ClinPred		0.077	T
GERP RS		2.3
Varity_R		0.24
gMVP		0.37

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

Other links and lift over

dbSNP: rs763233743; hg19: chr4-3465109;