4-3476293-C-T

Variant summary

Our verdict is Benign. Variant got -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:2
• Conservation: PhyloP100: 0.315

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]

LOC105374355 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 262876.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-3476293-C-T is described in Lovd as [Benign].
• 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/exons	MANE	UniProt
DOK7	NM_173660.5	c.332-49C>T		intron_variant		ENST00000340083.6
LOC105374355	XR_007057994.1	n.865+8G>A		splice_region_variant, intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DOK7	ENST00000340083.6	c.332-49C>T		intron_variant		1	NM_173660.5	P1

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

GnomAD3 exomes AF: 0.0000414 AC: 7 AN: 169116 Hom.: 1 AF XY: 0.0000531 AC XY: 5 AN XY: 94116

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 SAS exome AF: 0.00

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

Gnomad4 AFR exome AF: 0.0803

Gnomad4 AMR exome AF: 0.217

Gnomad4 ASJ exome AF: 0.0668

Gnomad4 EAS exome AF: 0.310

Gnomad4 SAS exome AF: 0.104

Gnomad4 FIN exome AF: 0.118

Gnomad4 NFE exome AF: 0.0551

Gnomad4 OTH exome AF: 0.0745

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

Gnomad4 AFR AF: 0.115

Gnomad4 AMR AF: 0.166

Gnomad4 ASJ AF: 0.0874

Gnomad4 EAS AF: 0.249

Gnomad4 SAS AF: 0.100

Gnomad4 FIN AF: 0.136

Gnomad4 NFE AF: 0.130

Gnomad4 OTH AF: 0.129

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 28, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
Cadd	Benign	7.0
Dann	Benign	0.79

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: rs114112298; hg19: chr4-3478020;