rs201304841

chr4-3493077-G-Achr4-3493077-G-Cchr4-3493077-G-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.1091G>A(p.Arg364Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000603 in 1,576,118 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R364W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00049 (2 hom., cov: 34)
  • Exomes 𝑓: 0.00062 (9 hom.)
• Consequence: DOK7 NM_173660.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.93

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=0.0062399507).
• BP6: Variant 4-3493077-G-A is Benign according to our data. Variant chr4-3493077-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 262866.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-3493077-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000486 (74/152348) while in subpopulation SAS AF= 0.0087 (42/4830). AF 95% confidence interval is 0.00661. There are 2 homozygotes in gnomad4. There are 47 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DOK7	NM_173660.5	c.1091G>A	p.Arg364Gln	missense_variant	7/7	ENST00000340083.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DOK7	ENST00000340083.6	c.1091G>A	p.Arg364Gln	missense_variant	7/7	1	NM_173660.5	P1
DOK7	ENST00000643608.1	c.659G>A	p.Arg220Gln	missense_variant	5/8
DOK7	ENST00000515886.5	c.161G>A	p.Arg54Gln	missense_variant	4/4	2
DOK7	ENST00000507039.5	c.*312G>A		3_prime_UTR_variant	7/7	2

Frequencies

GnomAD3 genomes AF: 0.000480 AC: 73 AN: 152230 Hom.: 2 Cov.: 34

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000785

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00848

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00134 AC: 246 AN: 183544 Hom.: 1 AF XY: 0.00170 AC XY: 171 AN XY: 100798

Gnomad AFR exome AF: 0.0000946

Gnomad AMR exome AF: 0.000904

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000144

Gnomad SAS exome AF: 0.00769

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000190

Gnomad OTH exome AF: 0.000611

GnomAD4 exome AF: 0.000615 AC: 876 AN: 1423770 Hom.: 9 Cov.: 111 AF XY: 0.000851 AC XY: 601 AN XY: 706098

Gnomad4 AFR exome AF: 0.000243

Gnomad4 AMR exome AF: 0.000798

Gnomad4 ASJ exome AF: 0.0000391

Gnomad4 EAS exome AF: 0.000238

Gnomad4 SAS exome AF: 0.00800

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000100

Gnomad4 OTH exome AF: 0.000676

GnomAD4 genome AF: 0.000486 AC: 74 AN: 152348 Hom.: 2 Cov.: 34 AF XY: 0.000631 AC XY: 47 AN XY: 74496

Gnomad4 AFR AF: 0.0000962

Gnomad4 AMR AF: 0.000784

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00870

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000191

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000314 Hom.: 0

Bravo AF: 0.000355

ExAC AF: 0.00127 AC: 151

Asia WGS AF: 0.00433 AC: 15 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

May 26, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.43
Cadd	Benign	16
Dann	Uncertain	1.0
DEOGEN2	Benign	0.076	T;.;.
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.41
FATHMM_MKL	Benign	0.35	N
LIST_S2	Benign	0.81	T;T;T
MetaRNN	Benign	0.0062	T;T;T
MetaSVM	Benign	-0.88	T
MutationAssessor	Uncertain	2.1	M;.;.
MutationTaster	Benign	1.0	D;N;N
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-1.5	N;.;.
REVEL	Benign	0.076
Sift	Benign	0.30	T;.;.
Sift4G	Benign	0.25	T;.;.
Polyphen		0.0050	B;.;.
Vest4		0.10
MVP		0.69
MPC		0.0043
ClinPred		0.011	T
GERP RS		-0.41
Varity_R		0.064
gMVP		0.091

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: rs201304841; hg19: chr4-3494804;