rs779508279

Positions:

• chr4-3493322-TGGCTGGGCACGAGAC-T

Variant summary

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

The NM_173660.5(DOK7):​c.1340_1354del​(p.Leu447_Arg451del) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.0000368 in 1,603,934 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000034 (0 hom.)
• Consequence: DOK7 NM_173660.5 inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 4.44

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: Nonframeshift variant in NON repetitive region in NM_173660.5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DOK7	NM_173660.5	c.1340_1354del	p.Leu447_Arg451del	inframe_deletion	7/7	ENST00000340083.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DOK7	ENST00000340083.6	c.1340_1354del	p.Leu447_Arg451del	inframe_deletion	7/7	1	NM_173660.5	P1
DOK7	ENST00000515886.5	c.410_424del	p.Leu137_Arg141del	inframe_deletion	4/4	2
DOK7	ENST00000643608.1	c.908_922del	p.Leu303_Arg307del	inframe_deletion	5/8
DOK7	ENST00000507039.5	c.*561_*575del		3_prime_UTR_variant	7/7	2

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152196 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000523

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000364 AC: 8 AN: 219718 Hom.: 0 AF XY: 0.0000576 AC XY: 7 AN XY: 121546

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000137

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000424

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000338 AC: 49 AN: 1451738 Hom.: 0 AF XY: 0.0000347 AC XY: 25 AN XY: 721222

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000685

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000117

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000316

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152196 Hom.: 0 Cov.: 34 AF XY: 0.0000807 AC XY: 6 AN XY: 74354

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000843 Hom.: 0

Bravo AF: 0.000162

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The DOK7 p.Leu137_Arg141del variant was not identified in the literature but was identified in dbSNP (ID: rs779508279) and ClinVar (classified as uncertain significance by Invitae). The variant was identified in control databases in 10 of 251084 chromosomes at a frequency of 0.00003983 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: South Asian in 4 of 29126 chromosomes (freq: 0.000137), European (non-Finnish) in 5 of 109750 chromosomes (freq: 0.000046) and Latino in 1 of 33670 chromosomes (freq: 0.00003), but was not observed in the African, Ashkenazi Jewish, East Asian, European (Finnish), or Other populations. This variant is an in-frame deletion resulting in the removal of codons 137 to 141; the impact of this alteration on DOK7 protein function is not known. The variant occurs outside of the splicing consensus sequence and three of four in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 26, 2019	- -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 27, 2022

This variant, c.1340_1354del, results in the deletion of 5 amino acid(s) of the DOK7 protein (p.Leu447_Arg451del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs779508279, gnomAD 0.01%). 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: 465675). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs779508279; hg19: chr4-3495049;