chr4-3493120-G-A

Position:

• chr4-3493120-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_173660.5(DOK7):​c.1134G>A​(p.Ala378=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.208 in 1,590,450 control chromosomes in the GnomAD database, including 38,311 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (3380 hom., cov: 34)
  • Exomes 𝑓: 0.21 (34931 hom.)
• Consequence: DOK7 NM_173660.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.09

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 4-3493120-G-A is Benign according to our data. Variant chr4-3493120-G-A is described in ClinVar as [Benign]. Clinvar id is 128905.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-3493120-G-A is described in Lovd as [Benign]. Variant chr4-3493120-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-1.09 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.495 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DOK7	NM_173660.5	c.1134G>A	p.Ala378=	synonymous_variant	7/7	ENST00000340083.6	NP_775931.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DOK7	ENST00000340083.6	c.1134G>A	p.Ala378=	synonymous_variant	7/7	1	NM_173660.5	ENSP00000344432	P1
DOK7	ENST00000643608.1	c.702G>A	p.Ala234=	synonymous_variant	5/8			ENSP00000495701
DOK7	ENST00000515886.5	c.204G>A	p.Ala68=	synonymous_variant	4/4	2		ENSP00000492194
DOK7	ENST00000507039.5	c.*355G>A		3_prime_UTR_variant	7/7	2		ENSP00000423614

Frequencies

GnomAD3 genomes AF: 0.182 AC: 27667 AN: 152054 Hom.: 3385 Cov.: 34

Gnomad AFR AF: 0.0539

Gnomad AMI AF: 0.279

Gnomad AMR AF: 0.146

Gnomad ASJ AF: 0.199

Gnomad EAS AF: 0.512

Gnomad SAS AF: 0.223

Gnomad FIN AF: 0.380

Gnomad MID AF: 0.180

Gnomad NFE AF: 0.207

Gnomad OTH AF: 0.186

GnomAD3 exomes AF: 0.222 AC: 45117 AN: 203522 Hom.: 5908 AF XY: 0.224 AC XY: 25117 AN XY: 112218

Gnomad AFR exome AF: 0.0533

Gnomad AMR exome AF: 0.142

Gnomad ASJ exome AF: 0.210

Gnomad EAS exome AF: 0.490

Gnomad SAS exome AF: 0.211

Gnomad FIN exome AF: 0.378

Gnomad NFE exome AF: 0.204

Gnomad OTH exome AF: 0.211

GnomAD4 exome AF: 0.210 AC: 302498 AN: 1438278 Hom.: 34931 Cov.: 113 AF XY: 0.211 AC XY: 150616 AN XY: 714238

Gnomad4 AFR exome AF: 0.0469

Gnomad4 AMR exome AF: 0.140

Gnomad4 ASJ exome AF: 0.211

Gnomad4 EAS exome AF: 0.505

Gnomad4 SAS exome AF: 0.206

Gnomad4 FIN exome AF: 0.378

Gnomad4 NFE exome AF: 0.201

Gnomad4 OTH exome AF: 0.210

GnomAD4 genome AF: 0.182 AC: 27665 AN: 152172 Hom.: 3380 Cov.: 34 AF XY: 0.189 AC XY: 14091 AN XY: 74404

Gnomad4 AFR AF: 0.0538

Gnomad4 AMR AF: 0.146

Gnomad4 ASJ AF: 0.199

Gnomad4 EAS AF: 0.511

Gnomad4 SAS AF: 0.223

Gnomad4 FIN AF: 0.380

Gnomad4 NFE AF: 0.207

Gnomad4 OTH AF: 0.186

Alfa AF: 0.168 Hom.: 1030

Bravo AF: 0.160

Asia WGS AF: 0.363 AC: 1266 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 23, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 03, 2021	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 19, 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. -

Fetal akinesia deformation sequence 1;C1850792:Congenital myasthenic syndrome 10 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.27
DANN	Benign	0.77

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: rs6831659; hg19: chr4-3494847; COSMIC: COSV60771666; COSMIC: COSV60771666;