rs1553850437

Variant names:

• chr4-3493501-A-G
• rs1553850437
• NM_173660.5:c.1515A>G

Variant summary

Our verdict is Uncertain significance. The variant received 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 (★). Synonymous variant affecting the same amino acid position has been classified as Likely benign.

• 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
• Publications: 0 publications found

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: ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
• fetal akinesia deformation sequence 3

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• fetal akinesia deformation sequence 1

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• postsynaptic congenital myasthenic syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_173660.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DOK7	NM_173660.5	MANE Select	c.1515A>G	p.Ter505Trpext*?	stop_lost	Exon 7 of 7	NP_775931.3
	DOK7	NM_001256896.2		c.585A>G	p.Ter195Trpext*?	stop_lost	Exon 4 of 4	NP_001243825.1	A0A1W2PRA3
	DOK7	NM_001164673.2		c.*736A>G		3_prime_UTR	Exon 7 of 7	NP_001158145.1	Q18PE1-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DOK7	ENST00000340083.6	TSL:1 MANE Select	c.1515A>G	p.Ter505Trpext*?	stop_lost	Exon 7 of 7	ENSP00000344432.5	Q18PE1-1
	DOK7	ENST00000515886.5	TSL:2	c.585A>G	p.Ter195Trpext*?	stop_lost	Exon 4 of 4	ENSP00000492194.1	A0A1W2PRA3
	DOK7	ENST00000507039.5	TSL:2	c.*736A>G		3_prime_UTR	Exon 7 of 7	ENSP00000423614.1	Q18PE1-4

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD4 exome Cov.: 87

GnomAD4 genome Cov.: 35

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Fetal akinesia deformation sequence 1;C1850792:Congenital myasthenic syndrome 10 (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		1.8
Vest4		0.043
GERP RS		2.4
Mutation Taster		=8/192	disease causing

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

Other links and lift over

dbSNP: rs1553850437; hg19: chr4-3495228;