4-3463346-G-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.-30G>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.102 in 1,447,188 control chromosomes in the GnomAD database, including 8,816 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.076 (678 hom., cov: 32)
  • Exomes 𝑓: 0.10 (8138 hom.)
• Consequence: DOK7 NM_173660.5 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.61

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 4-3463346-G-T is Benign according to our data. Variant chr4-3463346-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 262861.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-3463346-G-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.216 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DOK7	NM_173660.5	c.-30G>T		5_prime_UTR_variant	1/7	ENST00000340083.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DOK7	ENST00000340083.6	c.-30G>T		5_prime_UTR_variant	1/7	1	NM_173660.5	P1

Frequencies

GnomAD3 genomes AF: 0.0759 AC: 11521 AN: 151812 Hom.: 677 Cov.: 32

Gnomad AFR AF: 0.0176

Gnomad AMI AF: 0.0352

Gnomad AMR AF: 0.0858

Gnomad ASJ AF: 0.128

Gnomad EAS AF: 0.0280

Gnomad SAS AF: 0.228

Gnomad FIN AF: 0.0810

Gnomad MID AF: 0.0828

Gnomad NFE AF: 0.0993

Gnomad OTH AF: 0.0681

GnomAD3 exomes AF: 0.113 AC: 9379 AN: 83258 Hom.: 698 AF XY: 0.118 AC XY: 5632 AN XY: 47570

Gnomad AFR exome AF: 0.0153

Gnomad AMR exome AF: 0.116

Gnomad ASJ exome AF: 0.116

Gnomad EAS exome AF: 0.0322

Gnomad SAS exome AF: 0.234

Gnomad FIN exome AF: 0.0818

Gnomad NFE exome AF: 0.107

Gnomad OTH exome AF: 0.101

GnomAD4 exome AF: 0.105 AC: 135896 AN: 1295270 Hom.: 8138 Cov.: 32 AF XY: 0.108 AC XY: 68873 AN XY: 637794

Gnomad4 AFR exome AF: 0.0151

Gnomad4 AMR exome AF: 0.104

Gnomad4 ASJ exome AF: 0.114

Gnomad4 EAS exome AF: 0.0213

Gnomad4 SAS exome AF: 0.231

Gnomad4 FIN exome AF: 0.0742

Gnomad4 NFE exome AF: 0.103

Gnomad4 OTH exome AF: 0.101

GnomAD4 genome AF: 0.0759 AC: 11527 AN: 151918 Hom.: 678 Cov.: 32 AF XY: 0.0784 AC XY: 5820 AN XY: 74246

Gnomad4 AFR AF: 0.0175

Gnomad4 AMR AF: 0.0863

Gnomad4 ASJ AF: 0.128

Gnomad4 EAS AF: 0.0283

Gnomad4 SAS AF: 0.227

Gnomad4 FIN AF: 0.0810

Gnomad4 NFE AF: 0.0994

Gnomad4 OTH AF: 0.0670

Alfa AF: 0.0438 Hom.: 34

Bravo AF: 0.0684

Asia WGS AF: 0.109 AC: 369 AN: 3368

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 20, 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	PreventionGenetics, part of Exact Sciences	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
Cadd	Benign	16
Dann	Benign	0.83

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: rs146168804; hg19: chr4-3465073;