rs191800156

Positions:

• chr4-3463370-C-G

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_173660.5(DOK7):​c.-6C>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0246 in 1,487,404 control chromosomes in the GnomAD database, including 527 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (23 hom., cov: 31)
  • Exomes 𝑓: 0.025 (504 hom.)
• Consequence: DOK7 NM_173660.5 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 2.69

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 Benign. Variant got -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.25).
• BP6: Variant 4-3463370-C-G is Benign according to our data. Variant chr4-3463370-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 193509.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-3463370-C-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0175 (2626/149922) while in subpopulation NFE AF= 0.0268 (1813/67748). AF 95% confidence interval is 0.0257. There are 23 homozygotes in gnomad4. There are 1197 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 23 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DOK7	NM_173660.5	c.-6C>G		5_prime_UTR_variant	1/7	ENST00000340083.6	NP_775931.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DOK7	ENST00000340083	c.-6C>G		5_prime_UTR_variant	1/7	1	NM_173660.5	ENSP00000344432.5

Frequencies

GnomAD3 genomes AF: 0.0175 AC: 2625 AN: 149822 Hom.: 23 Cov.: 31

Gnomad AFR AF: 0.00534

Gnomad AMI AF: 0.0254

Gnomad AMR AF: 0.0219

Gnomad ASJ AF: 0.0156

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00814

Gnomad FIN AF: 0.0113

Gnomad MID AF: 0.00987

Gnomad NFE AF: 0.0268

Gnomad OTH AF: 0.0179

GnomAD3 exomes AF: 0.0149 AC: 1799 AN: 121120 Hom.: 21 AF XY: 0.0148 AC XY: 1020 AN XY: 69074

Gnomad AFR exome AF: 0.00288

Gnomad AMR exome AF: 0.00915

Gnomad ASJ exome AF: 0.0144

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00470

Gnomad FIN exome AF: 0.0129

Gnomad NFE exome AF: 0.0220

Gnomad OTH exome AF: 0.0187

GnomAD4 exome AF: 0.0253 AC: 33901 AN: 1337482 Hom.: 504 Cov.: 33 AF XY: 0.0250 AC XY: 16523 AN XY: 662094

Gnomad4 AFR exome AF: 0.00419

Gnomad4 AMR exome AF: 0.0109

Gnomad4 ASJ exome AF: 0.0160

Gnomad4 EAS exome AF: 0.0000306

Gnomad4 SAS exome AF: 0.00556

Gnomad4 FIN exome AF: 0.0124

Gnomad4 NFE exome AF: 0.0292

Gnomad4 OTH exome AF: 0.0215

GnomAD4 genome AF: 0.0175 AC: 2626 AN: 149922 Hom.: 23 Cov.: 31 AF XY: 0.0164 AC XY: 1197 AN XY: 73052

Gnomad4 AFR AF: 0.00532

Gnomad4 AMR AF: 0.0220

Gnomad4 ASJ AF: 0.0156

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00815

Gnomad4 FIN AF: 0.0113

Gnomad4 NFE AF: 0.0268

Gnomad4 OTH AF: 0.0177

Alfa AF: 0.0195 Hom.: 5

Bravo AF: 0.0176

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 11, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 29, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 24, 2017	- -

not provided Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

DOK7-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 26, 2020

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.25
CADD	Benign	20
DANN	Benign	0.96

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: rs191800156; hg19: chr4-3465097;