4-3473468-A-T

Variant names:

• chr4-3473468-A-T
• rs550137245
• NM_173660.5:c.163A>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_173660.5(DOK7):​c.163A>T​(p.Ser55Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000248 in 1,611,018 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S55G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: DOK7 NM_173660.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.28
• Publications: 0 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 -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.21305451).

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.163A>T	p.Ser55Cys	missense	Exon 3 of 7	NP_775931.3
	DOK7	NM_001301071.2		c.163A>T	p.Ser55Cys	missense	Exon 3 of 10	NP_001288000.1	Q18PE1-3
	DOK7	NM_001164673.2		c.163A>T	p.Ser55Cys	missense	Exon 3 of 7	NP_001158145.1	Q18PE1-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DOK7	ENST00000340083.6	TSL:1 MANE Select	c.163A>T	p.Ser55Cys	missense	Exon 3 of 7	ENSP00000344432.5	Q18PE1-1
	DOK7	ENST00000507039.5	TSL:2	c.163A>T	p.Ser55Cys	missense	Exon 3 of 7	ENSP00000423614.1	Q18PE1-4
	DOK7	ENST00000643608.1		c.100+9917A>T		intron	N/A	ENSP00000495701.1	A0A2R8Y701

Frequencies

GnomAD3 genomes AF: 0.000177 AC: 27 AN: 152266 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00177

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000484 AC: 12 AN: 248044 AF XY: 0.0000296

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000348

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000891 AC: 13 AN: 1458752 Hom.: 0 Cov.: 34 AF XY: 0.00000551 AC XY: 4 AN XY: 725684

African (AFR) AF: 0.00 AC: 0 AN: 33404

American (AMR) AF: 0.000268 AC: 12 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.00 AC: 0 AN: 86168

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52546

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4186

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111734

Other (OTH) AF: 0.0000166 AC: 1 AN: 60198

GnomAD4 genome AF: 0.000177 AC: 27 AN: 152266 Hom.: 0 Cov.: 34 AF XY: 0.000282 AC XY: 21 AN XY: 74400

African (AFR) AF: 0.00 AC: 0 AN: 41474

American (AMR) AF: 0.00177 AC: 27 AN: 15292

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10632

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68040

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000200

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Fetal akinesia deformation sequence 1;C1850792:Congenital myasthenic syndrome 10 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.29	T
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.20
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.84	T
M_CAP	Uncertain	0.094	D
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-0.66	T
MutationAssessor	Benign	1.9	M
PhyloP100		2.3
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-3.4	D
REVEL	Benign	0.26
Sift	Uncertain	0.0070	D
Sift4G	Benign	0.071	T
Polyphen		0.044	B
Vest4		0.39
MutPred		0.44		Loss of disorder (P = 0.0011)
MVP		0.72
MPC		0.011
ClinPred		0.14	T
GERP RS		2.5
Varity_R		0.19
gMVP		0.38
Mutation Taster		=93/7	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: rs550137245; hg19: chr4-3475195;