rs77051823

chr4-3473663-G-A

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.331+27G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.117 in 1,519,254 control chromosomes in the GnomAD database, including 11,609 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.098 (957 hom., cov: 33)
  • Exomes 𝑓: 0.12 (10652 hom.)
• Consequence: DOK7 NM_173660.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.95

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=-0.89).
• BP6: Variant 4-3473663-G-A is Benign according to our data. Variant chr4-3473663-G-A is described in ClinVar as [Benign]. Clinvar id is 262873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-3473663-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) 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.331+27G>A		intron_variant		ENST00000340083.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DOK7	ENST00000340083.6	c.331+27G>A		intron_variant		1	NM_173660.5	P1

Frequencies

GnomAD3 genomes AF: 0.0980 AC: 14913 AN: 152176 Hom.: 956 Cov.: 33

Gnomad AFR AF: 0.0252

Gnomad AMI AF: 0.0318

Gnomad AMR AF: 0.135

Gnomad ASJ AF: 0.0772

Gnomad EAS AF: 0.227

Gnomad SAS AF: 0.104

Gnomad FIN AF: 0.123

Gnomad MID AF: 0.122

Gnomad NFE AF: 0.122

Gnomad OTH AF: 0.0990

GnomAD3 exomes AF: 0.135 AC: 18770 AN: 139488 Hom.: 1503 AF XY: 0.132 AC XY: 9805 AN XY: 74194

Gnomad AFR exome AF: 0.0220

Gnomad AMR exome AF: 0.193

Gnomad ASJ exome AF: 0.0762

Gnomad EAS exome AF: 0.236

Gnomad SAS exome AF: 0.108

Gnomad FIN exome AF: 0.128

Gnomad NFE exome AF: 0.123

Gnomad OTH exome AF: 0.117

GnomAD4 exome AF: 0.119 AC: 162894 AN: 1366960 Hom.: 10652 Cov.: 33 AF XY: 0.119 AC XY: 79406 AN XY: 668394

Gnomad4 AFR exome AF: 0.0198

Gnomad4 AMR exome AF: 0.181

Gnomad4 ASJ exome AF: 0.0722

Gnomad4 EAS exome AF: 0.272

Gnomad4 SAS exome AF: 0.104

Gnomad4 FIN exome AF: 0.121

Gnomad4 NFE exome AF: 0.117

Gnomad4 OTH exome AF: 0.111

GnomAD4 genome AF: 0.0979 AC: 14907 AN: 152294 Hom.: 957 Cov.: 33 AF XY: 0.101 AC XY: 7513 AN XY: 74472

Gnomad4 AFR AF: 0.0251

Gnomad4 AMR AF: 0.134

Gnomad4 ASJ AF: 0.0772

Gnomad4 EAS AF: 0.227

Gnomad4 SAS AF: 0.104

Gnomad4 FIN AF: 0.123

Gnomad4 NFE AF: 0.122

Gnomad4 OTH AF: 0.0975

Alfa AF: 0.111 Hom.: 193

Bravo AF: 0.0972

Asia WGS AF: 0.131 AC: 453 AN: 3478

ClinVar

Significance: 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

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- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 28, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
Cadd	Benign	0.62
Dann	Benign	0.54

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: rs77051823; hg19: chr4-3475390; COSMIC: COSV60771511;