rs201304841

Variant names:

• chr4-3493077-G-A
• rs201304841
• NM_173660.5:c.1091G>A

Your query was ambiguous. Multiple possible variants found:

• chr4-3493077-G-A
• chr4-3493077-G-C
• chr4-3493077-G-T

Variant summary

Our verdict is Benign. The variant received -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. 13/21 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:4
• Conservation: PhyloP100: 1.93
• Publications: 1 publications found

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]

DOK7 Gene-Disease associations (from GenCC):

• congenital myasthenic syndrome 10

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), PanelApp Australia
• fetal akinesia deformation sequence 3

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• fetal akinesia deformation sequence 1

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• postsynaptic congenital myasthenic syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 262866.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_173660.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DOK7	NM_173660.5	MANE Select	c.1091G>A	p.Arg364Gln	missense	Exon 7 of 7	NP_775931.3
	DOK7	NM_001301071.2		c.1091G>A	p.Arg364Gln	missense	Exon 7 of 10	NP_001288000.1
	DOK7	NM_001363811.2		c.659G>A	p.Arg220Gln	missense	Exon 5 of 8	NP_001350740.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DOK7	ENST00000340083.6	TSL:1 MANE Select	c.1091G>A	p.Arg364Gln	missense	Exon 7 of 7	ENSP00000344432.5
	DOK7	ENST00000643608.1		c.659G>A	p.Arg220Gln	missense	Exon 5 of 8	ENSP00000495701.1
	DOK7	ENST00000515886.5	TSL:2	c.161G>A	p.Arg54Gln	missense	Exon 4 of 4	ENSP00000492194.1

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

GnomAD2 exomes AF: 0.00134 AC: 246 AN: 183544 AF XY: 0.00170

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 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

African (AFR) AF: 0.000243 AC: 8 AN: 32918

American (AMR) AF: 0.000798 AC: 32 AN: 40096

Ashkenazi Jewish (ASJ) AF: 0.0000391 AC: 1 AN: 25550

East Asian (EAS) AF: 0.000238 AC: 9 AN: 37852

South Asian (SAS) AF: 0.00800 AC: 660 AN: 82482

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42574

Middle Eastern (MID) AF: 0.00279 AC: 16 AN: 5730

European-Non Finnish (NFE) AF: 0.000100 AC: 110 AN: 1097408

Other (OTH) AF: 0.000676 AC: 40 AN: 59160

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

African (AFR) AF: 0.0000962 AC: 4 AN: 41580

American (AMR) AF: 0.000784 AC: 12 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00870 AC: 42 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 68030

Other (OTH) AF: 0.00142 AC: 3 AN: 2112

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:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

May 26, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

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
MetaRNN	Benign	0.0062	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		1.9
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
Mutation Taster		=97/3	polymorphism

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

Other links and lift over

dbSNP: rs201304841; hg19: chr4-3494804; COSMIC: COSV108879743; COSMIC: COSV108879743;