rs1553850437

Positions:

• chr4-3493501-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PM4

The NM_173660.5(DOK7):​c.1515A>G​(p.Ter505Trpext*?) variant causes a stop lost change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 35)
• Consequence: DOK7 NM_173660.5 stop_lost
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.79

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Stoplost variant in NM_173660.5 Downstream stopcodon found after 527 codons.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DOK7	NM_173660.5	c.1515A>G	p.Ter505Trpext*?	stop_lost	7/7	ENST00000340083.6	NP_775931.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DOK7	ENST00000340083.6	c.1515A>G	p.Ter505Trpext*?	stop_lost	7/7	1	NM_173660.5	ENSP00000344432.5
DOK7	ENST00000515886.5	c.585A>G	p.Ter195Trpext*?	stop_lost	4/4	2		ENSP00000492194.1
DOK7	ENST00000507039.5	c.*736A>G		3_prime_UTR_variant	7/7	2		ENSP00000423614.1
DOK7	ENST00000643608.1	c.1065+18A>G		intron_variant				ENSP00000495701.1

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD4 exome Cov.: 87

GnomAD4 genome Cov.: 35

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

Aug 06, 2016

This sequence change disrupts the translational stop signal of the DOK7 mRNA. It is expected to extend the length of the DOK7 protein by 182 additional amino acid residues (p.*505Trpext*182). While this variant is not present in population databases, the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. A different variant (c.1513T>C) giving rise to the same protein effect observed here (p.*505Trpext*182) has been reported in a patient affected with congenital myasthenic syndrome (PMID: 18626973). This variant was observed on the opposite chromosome (in trans) from a likely pathogenic variant (PMID: 18626973). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. In summary, this is a novel variant that extends the reading frame of the DOK7 protein. While a similar variant has been reported in an affected individual, the evidence is currently insufficient to conclusively determine this variant's role in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	17
DANN	Benign	0.76
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Benign	0.63	D
Vest4		0.043
GERP RS		2.4

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: rs1553850437; hg19: chr4-3495228;