chr4-3493411-G-T

Variant names:

• chr4-3493411-G-T
• rs777626370
• NM_173660.5:c.1425G>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BS1_Supporting BS2_Supporting

The NM_173660.5(DOK7):​c.1425G>T​(p.Trp475Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000254 in 1,598,000 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00027 (0 hom., cov: 35)
  • Exomes 𝑓: 0.00025 (2 hom.)
• Consequence: DOK7 NM_173660.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3 O:1
• Conservation: PhyloP100: 2.42
• 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: ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
• fetal akinesia deformation sequence 3

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.06621128).
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.000252 (365/1445682) while in subpopulation MID AF = 0.00534 (30/5622). AF 95% confidence interval is 0.00384. There are 2 homozygotes in GnomAdExome4. There are 186 alleles in the male GnomAdExome4 subpopulation. Median coverage is 88. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 2 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DOK7	NM_173660.5	MANE Select	c.1425G>T	p.Trp475Cys	missense	Exon 7 of 7	NP_775931.3
	DOK7	NM_001301071.2		c.1425G>T	p.Trp475Cys	missense	Exon 7 of 10	NP_001288000.1	Q18PE1-3
	DOK7	NM_001363811.2		c.993G>T	p.Trp331Cys	missense	Exon 5 of 8	NP_001350740.1	A0A2R8Y701

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DOK7	ENST00000340083.6	TSL:1 MANE Select	c.1425G>T	p.Trp475Cys	missense	Exon 7 of 7	ENSP00000344432.5	Q18PE1-1
	DOK7	ENST00000643608.1		c.993G>T	p.Trp331Cys	missense	Exon 5 of 8	ENSP00000495701.1	A0A2R8Y701
	DOK7	ENST00000515886.5	TSL:2	c.495G>T	p.Trp165Cys	missense	Exon 4 of 4	ENSP00000492194.1	A0A1W2PRA3

Frequencies

GnomAD3 genomes AF: 0.000269 AC: 41 AN: 152200 Hom.: 0 Cov.: 35

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00170

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000243 AC: 51 AN: 209818 AF XY: 0.000241

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000572

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000521

Gnomad NFE exome AF: 0.000292

Gnomad OTH exome AF: 0.000949

GnomAD4 exome AF: 0.000252 AC: 365 AN: 1445682 Hom.: 2 Cov.: 88 AF XY: 0.000259 AC XY: 186 AN XY: 718070

African (AFR) AF: 0.000151 AC: 5 AN: 33180

American (AMR) AF: 0.000798 AC: 34 AN: 42586

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25814

East Asian (EAS) AF: 0.00 AC: 0 AN: 39104

South Asian (SAS) AF: 0.0000355 AC: 3 AN: 84510

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50542

Middle Eastern (MID) AF: 0.00534 AC: 30 AN: 5622

European-Non Finnish (NFE) AF: 0.000239 AC: 264 AN: 1104672

Other (OTH) AF: 0.000486 AC: 29 AN: 59652

GnomAD4 genome AF: 0.000269 AC: 41 AN: 152318 Hom.: 0 Cov.: 35 AF XY: 0.000201 AC XY: 15 AN XY: 74484

African (AFR) AF: 0.0000722 AC: 3 AN: 41576

American (AMR) AF: 0.00170 AC: 26 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

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

European-Non Finnish (NFE) AF: 0.000176 AC: 12 AN: 68010

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000270 Hom.: 0

Bravo AF: 0.000465

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.000168 AC: 20

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Congenital myasthenic syndrome 10 (1)
-	1	-	Fetal akinesia deformation sequence 1;C1850792:Congenital myasthenic syndrome 10 (1)
-	1	-	not provided (1)
-	-	-	Congenital myasthenic syndrome 10;C4760599:Fetal akinesia deformation sequence 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	21
DANN	Benign	0.36
DEOGEN2	Benign	0.032	T
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.25
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.059	D
MetaRNN	Benign	0.066	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.4	L
PhyloP100		2.4
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.17
Sift	Benign	0.27	T
Sift4G	Benign	0.22	T
Polyphen		0.0	B
Vest4		0.22
MutPred		0.49		Loss of glycosylation at P474 (P = 0.0493)
MVP		0.69
MPC		0.016
ClinPred		0.081	T
GERP RS		2.8
Varity_R		0.30
gMVP		0.12
Mutation Taster		=96/4	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: rs777626370; hg19: chr4-3495138; COSMIC: COSV108186907; COSMIC: COSV108186907;