rs184556570

Positions:

• chr4-3493493-C-A
• chr4-3493493-C-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_173660.5(DOK7):​c.1507C>A​(p.Pro503Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000665 in 1,611,192 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00052 (1 hom., cov: 35)
  • Exomes 𝑓: 0.00068 (6 hom.)
• Consequence: DOK7 NM_173660.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 0.875

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007641524).
• BP6: Variant 4-3493493-C-A is Benign according to our data. Variant chr4-3493493-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 465680.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=1}. Variant chr4-3493493-C-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000518 (79/152372) while in subpopulation SAS AF= 0.00311 (15/4830). AF 95% confidence interval is 0.00191. There are 1 homozygotes in gnomad4. There are 40 alleles in male gnomad4 subpopulation. Median coverage is 35. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DOK7	NM_173660.5	c.1507C>A	p.Pro503Thr	missense_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.1507C>A	p.Pro503Thr	missense_variant	7/7	1	NM_173660.5	ENSP00000344432.5
DOK7	ENST00000515886.5	c.577C>A	p.Pro193Thr	missense_variant	4/4	2		ENSP00000492194.1
DOK7	ENST00000507039.5	c.*728C>A		3_prime_UTR_variant	7/7	2		ENSP00000423614.1
DOK7	ENST00000643608.1	c.1065+10C>A		intron_variant				ENSP00000495701.1

Frequencies

GnomAD3 genomes AF: 0.000519 AC: 79 AN: 152254 Hom.: 1 Cov.: 35

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000785

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00310

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000544

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00117 AC: 277 AN: 236896 Hom.: 5 AF XY: 0.00151 AC XY: 197 AN XY: 130580

Gnomad AFR exome AF: 0.0000717

Gnomad AMR exome AF: 0.000674

Gnomad ASJ exome AF: 0.00207

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00472

Gnomad FIN exome AF: 0.000283

Gnomad NFE exome AF: 0.000768

Gnomad OTH exome AF: 0.000856

GnomAD4 exome AF: 0.000681 AC: 993 AN: 1458820 Hom.: 6 Cov.: 88 AF XY: 0.000845 AC XY: 613 AN XY: 725558

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000852

Gnomad4 ASJ exome AF: 0.00153

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00430

Gnomad4 FIN exome AF: 0.000251

Gnomad4 NFE exome AF: 0.000400

Gnomad4 OTH exome AF: 0.000996

GnomAD4 genome AF: 0.000518 AC: 79 AN: 152372 Hom.: 1 Cov.: 35 AF XY: 0.000537 AC XY: 40 AN XY: 74510

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.000784

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00311

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.000544

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000533 Hom.: 0

Bravo AF: 0.000423

ExAC AF: 0.00113 AC: 136

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 11, 2018	This variant is associated with the following publications: (PMID: 22661499) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	DOK7: BP4, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 12, 2021

The c.1507C>A (p.P503T) alteration is located in exon 7 (coding exon 7) of the DOK7 gene. This alteration results from a C to A substitution at nucleotide position 1507, causing the proline (P) at amino acid position 503 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Congenital myasthenic syndrome 10;C4760599:Fetal akinesia deformation sequence 3 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 27, 2021

- -

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

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	21
DANN	Benign	0.92
DEOGEN2	Benign	0.082	T;.
Eigen	Uncertain	0.22
Eigen_PC	Benign	0.20
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.53	T;T
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.0076	T;T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	1.9	M;.
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.78	N;.
REVEL	Benign	0.097
Sift	Pathogenic	0.0	D;.
Sift4G	Benign	0.063	T;.
Polyphen		0.95	P;.
Vest4		0.29
MVP		0.69
MPC		0.019
ClinPred		0.031	T
GERP RS		3.6
Varity_R		0.22
gMVP		0.093

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: rs184556570; hg19: chr4-3495220;