4-3476293-C-T

Variant names:

• chr4-3476293-C-T
• rs114112298
• NM_173660.5:c.332-49C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_173660.5(DOK7):​c.332-49C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.131 in 119,506 control chromosomes in the GnomAD database, including 2,838 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (2838 hom., cov: 23)
  • Exomes 𝑓: 0.074 (15143 hom.)
  • Failed GnomAD Quality Control
• Consequence: DOK7 NM_173660.5 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.315
• Publications: 2 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: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), PanelApp Australia
• fetal akinesia deformation sequence 3

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

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

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

LOC105374355 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 4-3476293-C-T is Benign according to our data. Variant chr4-3476293-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 262876.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.236 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DOK7	NM_173660.5	c.332-49C>T		intron_variant	Intron 3 of 6	ENST00000340083.6	NP_775931.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DOK7	ENST00000340083.6	c.332-49C>T		intron_variant	Intron 3 of 6	1	NM_173660.5	ENSP00000344432.5

Frequencies

GnomAD3 genomes AF: 0.131 AC: 15614 AN: 119432 Hom.: 2837 Cov.: 23

Gnomad AFR AF: 0.115

Gnomad AMI AF: 0.0292

Gnomad AMR AF: 0.166

Gnomad ASJ AF: 0.0874

Gnomad EAS AF: 0.250

Gnomad SAS AF: 0.0997

Gnomad FIN AF: 0.136

Gnomad MID AF: 0.135

Gnomad NFE AF: 0.130

Gnomad OTH AF: 0.130

GnomAD2 exomes AF: 0.0000414 AC: 7 AN: 169116 AF XY: 0.0000531

Gnomad AFR exome AF: 0.0000919

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000193

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000505

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0738 AC: 63887 AN: 865788 Hom.: 15143 Cov.: 26 AF XY: 0.0771 AC XY: 33825 AN XY: 438980

African (AFR) AF: 0.0803 AC: 1679 AN: 20910

American (AMR) AF: 0.217 AC: 7072 AN: 32660

Ashkenazi Jewish (ASJ) AF: 0.0668 AC: 1060 AN: 15872

East Asian (EAS) AF: 0.310 AC: 5551 AN: 17932

South Asian (SAS) AF: 0.104 AC: 7397 AN: 70964

European-Finnish (FIN) AF: 0.118 AC: 2701 AN: 22852

Middle Eastern (MID) AF: 0.0693 AC: 254 AN: 3664

European-Non Finnish (NFE) AF: 0.0551 AC: 35672 AN: 647372

Other (OTH) AF: 0.0745 AC: 2501 AN: 33562

GnomAD4 genome AF: 0.131 AC: 15616 AN: 119506 Hom.: 2838 Cov.: 23 AF XY: 0.133 AC XY: 7539 AN XY: 56782

African (AFR) AF: 0.115 AC: 3629 AN: 31648

American (AMR) AF: 0.166 AC: 1777 AN: 10702

Ashkenazi Jewish (ASJ) AF: 0.0874 AC: 269 AN: 3078

East Asian (EAS) AF: 0.249 AC: 929 AN: 3730

South Asian (SAS) AF: 0.100 AC: 328 AN: 3270

European-Finnish (FIN) AF: 0.136 AC: 898 AN: 6614

Middle Eastern (MID) AF: 0.135 AC: 30 AN: 222

European-Non Finnish (NFE) AF: 0.130 AC: 7528 AN: 57864

Other (OTH) AF: 0.129 AC: 205 AN: 1590

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 28, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	7.0
DANN	Benign	0.79
PhyloP100		0.32
Mutation Taster		=100/0	polymorphism (auto)

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: rs114112298; hg19: chr4-3478020;