rs1553850025

Variant names:

• chr4-3492879-G-A
• rs1553850025
• NM_173660.5:c.893G>A

Your query was ambiguous. Multiple possible variants found:

• chr4-3492879-G-A
• chr4-3492879-G-C
• chr4-3492879-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001301071.2(DOK7):​c.893G>A​(p.Gly298Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000896 in 1,450,286 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. G298G) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000090 (0 hom.)
• Consequence: DOK7 NM_001301071.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.50
• 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: 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3102512).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001301071.2. 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.893G>A	p.Gly298Glu	missense	Exon 7 of 7	NP_775931.3
	DOK7	NM_001301071.2		c.893G>A	p.Gly298Glu	missense	Exon 7 of 10	NP_001288000.1
	DOK7	NM_001363811.2		c.461G>A	p.Gly154Glu	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.893G>A	p.Gly298Glu	missense	Exon 7 of 7	ENSP00000344432.5
	DOK7	ENST00000513995.1	TSL:1	n.551G>A		non_coding_transcript_exon	Exon 3 of 3
	DOK7	ENST00000643608.1		c.461G>A	p.Gly154Glu	missense	Exon 5 of 8	ENSP00000495701.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000896 AC: 13 AN: 1450286 Hom.: 0 Cov.: 111 AF XY: 0.0000111 AC XY: 8 AN XY: 720706

African (AFR) AF: 0.00 AC: 0 AN: 33280

American (AMR) AF: 0.0000229 AC: 1 AN: 43676

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25866

East Asian (EAS) AF: 0.00 AC: 0 AN: 39126

South Asian (SAS) AF: 0.00 AC: 0 AN: 84788

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49552

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.0000108 AC: 12 AN: 1108212

Other (OTH) AF: 0.00 AC: 0 AN: 60030

GnomAD4 genome Cov.: 34

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

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	0.12
BayesDel_addAF	Benign	-0.060	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.18	T
Eigen	Benign	0.068
Eigen_PC	Benign	0.036
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.62	T
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.31	T
MetaSVM	Benign	-0.44	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		3.5
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.15
Sift	Benign	0.15	T
Sift4G	Uncertain	0.010	D
Polyphen		0.42	B
Vest4		0.20
MutPred		0.15		Gain of glycosylation at T294 (P = 0.0155)
MVP		0.82
MPC		0.015
ClinPred		0.83	D
GERP RS		3.9
Varity_R		0.28
gMVP		0.086
Mutation Taster		=81/19	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: rs1553850025; hg19: chr4-3494606;