4-3463418-G-A

Position:

• chr4-3463418-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_173660.5(DOK7):​c.43G>A​(p.Asp15Asn) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000015 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: DOK7 NM_173660.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.09

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a domain PH (size 105) in uniprot entity DOK7_HUMAN there are 13 pathogenic changes around while only 3 benign (81%) in NM_173660.5
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DOK7	NM_173660.5	c.43G>A	p.Asp15Asn	missense_variant	1/7	ENST00000340083.6	NP_775931.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DOK7	ENST00000340083.6	c.43G>A	p.Asp15Asn	missense_variant	1/7	1	NM_173660.5	ENSP00000344432.5

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000151 AC: 2 AN: 1328486 Hom.: 0 Cov.: 46 AF XY: 0.00000305 AC XY: 2 AN XY: 656188

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000835

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

Bravo AF: 0.0000113

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

Labcorp Genetics (formerly Invitae), Labcorp

Jul 25, 2022

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 15 of the DOK7 protein (p.Asp15Asn). This variant is not present in population databases (gnomAD no frequency). 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: 956398). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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	Uncertain	0.53
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.26	.;T;.
Eigen	Uncertain	0.28
Eigen_PC	Benign	0.22
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Pathogenic	0.86	D
MetaRNN	Uncertain	0.43	T;T;T
MetaSVM	Benign	-0.33	T
MutationAssessor	Uncertain	2.3	M;M;.
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-2.9	D;D;.
REVEL	Uncertain	0.37
Sift	Uncertain	0.0070	D;D;.
Sift4G	Uncertain	0.013	D;D;.
Polyphen		0.97	.;D;.
Vest4		0.34
MutPred		0.29		Gain of MoRF binding (P = 0.0537);Gain of MoRF binding (P = 0.0537);Gain of MoRF binding (P = 0.0537);
MVP		0.80
MPC		0.0048
ClinPred		0.94	D
GERP RS		2.3
Varity_R		0.25
gMVP		0.39

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: rs1726072530; hg19: chr4-3465145;