chr4-3492873-A-T

Variant names:

• chr4-3492873-A-T
• rs6811423
• NM_173660.5:c.887A>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001256896.2(DOK7):​c.-44A>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 34)
• Consequence: DOK7 NM_001256896.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.28
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16166785).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001256896.2. 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.887A>T	p.Gln296Leu	missense	Exon 7 of 7	NP_775931.3
	DOK7	NM_001256896.2		c.-44A>T		5_prime_UTR_premature_start_codon_gain	Exon 4 of 4	NP_001243825.1	A0A1W2PRA3
	DOK7	NM_001301071.2		c.887A>T	p.Gln296Leu	missense	Exon 7 of 10	NP_001288000.1	Q18PE1-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DOK7	ENST00000340083.6	TSL:1 MANE Select	c.887A>T	p.Gln296Leu	missense	Exon 7 of 7	ENSP00000344432.5	Q18PE1-1
	DOK7	ENST00000513995.1	TSL:1	n.545A>T		non_coding_transcript_exon	Exon 3 of 3
	DOK7	ENST00000515886.5	TSL:2	c.-44A>T		5_prime_UTR_premature_start_codon_gain	Exon 4 of 4	ENSP00000492194.1	A0A1W2PRA3

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 106

GnomAD4 genome Cov.: 34

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	0.097
BayesDel_addAF	Benign	-0.069	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	16
DANN	Benign	0.79
DEOGEN2	Benign	0.19	T
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.44	N
LIST_S2	Benign	0.43	T
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	1.7	L
PhyloP100		1.3
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-3.1	D
REVEL	Benign	0.098
Sift	Benign	0.085	T
Sift4G	Benign	0.23	T
Polyphen		0.0	B
Vest4		0.17
MutPred		0.17		Gain of glycosylation at T294 (P = 0.0155)
MVP		0.75
MPC		0.0048
ClinPred		0.26	T
GERP RS		1.4
Varity_R		0.13
gMVP		0.15
Mutation Taster		=98/2	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: rs6811423; hg19: chr4-3494600;