rs16844470

chr4-3493337-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_173660.5(DOK7):c.1351C>T(p.Arg451Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00326 in 1,600,082 control chromosomes in the GnomAD database, including 79 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R451Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.013 (34 hom., cov: 34)
  • Exomes 𝑓: 0.0022 (45 hom.)
• Consequence: DOK7 NM_173660.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.02

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 (MetaRNN=0.0030781329).
• BP6: Variant 4-3493337-C-T is Benign according to our data. Variant chr4-3493337-C-T is described in ClinVar as [Benign]. Clinvar id is 128910.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-3493337-C-T is described in Lovd as [Likely_benign]. Variant chr4-3493337-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0135 (2052/152308) while in subpopulation AFR AF= 0.0432 (1798/41578). AF 95% confidence interval is 0.0416. There are 34 homozygotes in gnomad4. There are 944 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 34 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DOK7	NM_173660.5	c.1351C>T	p.Arg451Trp	missense_variant	7/7	ENST00000340083.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DOK7	ENST00000340083.6	c.1351C>T	p.Arg451Trp	missense_variant	7/7	1	NM_173660.5	P1
DOK7	ENST00000643608.1	c.919C>T	p.Arg307Trp	missense_variant	5/8
DOK7	ENST00000515886.5	c.421C>T	p.Arg141Trp	missense_variant	4/4	2
DOK7	ENST00000507039.5	c.*572C>T		3_prime_UTR_variant	7/7	2

Frequencies

GnomAD3 genomes AF: 0.0135 AC: 2048 AN: 152190 Hom.: 34 Cov.: 34

Gnomad AFR AF: 0.0433

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00949

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00128

Gnomad OTH AF: 0.00669

GnomAD3 exomes AF: 0.00362 AC: 773 AN: 213460 Hom.: 17 AF XY: 0.00309 AC XY: 365 AN XY: 118078

Gnomad AFR exome AF: 0.0433

Gnomad AMR exome AF: 0.00419

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000418

Gnomad FIN exome AF: 0.000105

Gnomad NFE exome AF: 0.000998

Gnomad OTH exome AF: 0.00343

GnomAD4 exome AF: 0.00219 AC: 3165 AN: 1447774 Hom.: 45 Cov.: 96 AF XY: 0.00210 AC XY: 1510 AN XY: 718856

Gnomad4 AFR exome AF: 0.0404

Gnomad4 AMR exome AF: 0.00413

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000256

Gnomad4 SAS exome AF: 0.000507

Gnomad4 FIN exome AF: 0.0000592

Gnomad4 NFE exome AF: 0.00123

Gnomad4 OTH exome AF: 0.00385

GnomAD4 genome AF: 0.0135 AC: 2052 AN: 152308 Hom.: 34 Cov.: 34 AF XY: 0.0127 AC XY: 944 AN XY: 74474

Gnomad4 AFR AF: 0.0432

Gnomad4 AMR AF: 0.00948

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.000282

Gnomad4 NFE AF: 0.00128

Gnomad4 OTH AF: 0.00662

Alfa AF: 0.00494 Hom.: 2

Bravo AF: 0.0152

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.0409 AC: 173

ESP6500EA AF: 0.00132 AC: 11

ExAC AF: 0.00371 AC: 437

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 16, 2014	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 03, 2017	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, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.34
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.37	T;.;.
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.34
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.82	T;T;T
MetaRNN	Benign	0.0031	T;T;T
MetaSVM	Benign	-0.86	T
MutationAssessor	Uncertain	2.1	M;.;.
MutationTaster	Benign	0.93	D;N;N
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-3.8	D;.;.
REVEL	Benign	0.15
Sift	Uncertain	0.010	D;.;.
Sift4G	Uncertain	0.021	D;.;.
Polyphen		0.27	B;.;.
Vest4		0.32
MVP		0.77
MPC		0.019
ClinPred		0.024	T
GERP RS		2.5
Varity_R		0.16
gMVP		0.15

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: rs16844470; hg19: chr4-3495064;