rs16844422

chr4-3485595-G-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_173660.5(DOK7):c.589G>A(p.Asp197Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00426 in 1,607,942 control chromosomes in the GnomAD database, including 228 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.022 (113 hom., cov: 34)
  • Exomes 𝑓: 0.0024 (115 hom.)
• Consequence: DOK7 NM_173660.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 9.24

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 -18 ACMG points.

• PM1: In a domain IRS-type PTB (size 105) in uniprot entity DOK7_HUMAN there are 40 pathogenic changes around while only 1 benign (98%) in NM_173660.5
• BP4: Computational evidence support a benign effect (MetaRNN=0.005733669).
• BP6: Variant 4-3485595-G-A is Benign according to our data. Variant chr4-3485595-G-A is described in ClinVar as [Benign]. Clinvar id is 128913.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-3485595-G-A is described in Lovd as [Benign]. Variant chr4-3485595-G-A is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0722 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DOK7	NM_173660.5	c.589G>A	p.Asp197Asn	missense_variant	5/7	ENST00000340083.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DOK7	ENST00000340083.6	c.589G>A	p.Asp197Asn	missense_variant	5/7	1	NM_173660.5	P1

Frequencies

GnomAD3 genomes AF: 0.0218 AC: 3324 AN: 152168 Hom.: 113 Cov.: 34

Gnomad AFR AF: 0.0744

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0101

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000661

Gnomad OTH AF: 0.0202

GnomAD3 exomes AF: 0.00579 AC: 1423 AN: 245954 Hom.: 47 AF XY: 0.00460 AC XY: 614 AN XY: 133408

Gnomad AFR exome AF: 0.0735

Gnomad AMR exome AF: 0.00545

Gnomad ASJ exome AF: 0.000101

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000234

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000449

Gnomad OTH exome AF: 0.00370

GnomAD4 exome AF: 0.00242 AC: 3516 AN: 1455656 Hom.: 115 Cov.: 33 AF XY: 0.00217 AC XY: 1568 AN XY: 724046

Gnomad4 AFR exome AF: 0.0755

Gnomad4 AMR exome AF: 0.00604

Gnomad4 ASJ exome AF: 0.000154

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000199

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000331

Gnomad4 OTH exome AF: 0.00551

GnomAD4 genome AF: 0.0219 AC: 3333 AN: 152286 Hom.: 113 Cov.: 34 AF XY: 0.0212 AC XY: 1580 AN XY: 74452

Gnomad4 AFR AF: 0.0744

Gnomad4 AMR AF: 0.0101

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000662

Gnomad4 OTH AF: 0.0199

Alfa AF: 0.0114 Hom.: 46

Bravo AF: 0.0243

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.0645 AC: 284

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.00726 AC: 881

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.000660

EpiControl AF: 0.000900

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 31, 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. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
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. -

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 06, 2017	- -

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	Pathogenic	0.72
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.20
Cadd	Pathogenic	33
Dann	Uncertain	0.99
DEOGEN2	Benign	0.26	T;.
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Pathogenic	0.98	D;D
MetaRNN	Benign	0.0057	T;T
MetaSVM	Benign	-0.73	T
MutationTaster	Benign	1.0	D;D;N
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-3.3	D;.
REVEL	Uncertain	0.41
Sift	Benign	0.037	D;.
Sift4G	Uncertain	0.011	D;.
Polyphen		1.0	D;.
Vest4		0.71
MVP		0.86
MPC		0.020
ClinPred		0.032	T
GERP RS		3.8
Varity_R		0.59
gMVP		0.70

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: rs16844422; hg19: chr4-3487322;