4-3463403-C-T

Variant names:

• chr4-3463403-C-T
• NM_173660.5:c.28C>T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_173660.5(DOK7):​c.28C>T​(p.Gln10*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. Q10Q) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: DOK7 NM_173660.5 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.361
• 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, Labcorp Genetics (formerly Invitae), ClinGen, Genomics England PanelApp, 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: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 126 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 4-3463403-C-T is Pathogenic according to our data. Variant chr4-3463403-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 2939697.Status of the report is criteria_provided_single_submitter, 1 stars.

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.28C>T	p.Gln10*	stop_gained	Exon 1 of 7	NP_775931.3
	DOK7	NM_001301071.2		c.28C>T	p.Gln10*	stop_gained	Exon 1 of 10	NP_001288000.1	Q18PE1-3
	DOK7	NM_001363811.2		c.28C>T	p.Gln10*	stop_gained	Exon 1 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.28C>T	p.Gln10*	stop_gained	Exon 1 of 7	ENSP00000344432.5	Q18PE1-1
	DOK7	ENST00000643608.1		c.28C>T	p.Gln10*	stop_gained	Exon 1 of 8	ENSP00000495701.1	A0A2R8Y701
	DOK7	ENST00000507039.5	TSL:2	c.28C>T	p.Gln10*	stop_gained	Exon 1 of 7	ENSP00000423614.1	Q18PE1-4

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1334410 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 659924

African (AFR) AF: 0.00 AC: 0 AN: 27206

American (AMR) AF: 0.00 AC: 0 AN: 24966

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22036

East Asian (EAS) AF: 0.00 AC: 0 AN: 32334

South Asian (SAS) AF: 0.00 AC: 0 AN: 71380

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35048

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3842

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1062470

Other (OTH) AF: 0.00 AC: 0 AN: 55128

GnomAD4 genome Cov.: 30

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

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
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	46
DANN	Uncertain	1.0
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.89	D
PhyloP100		0.36
Vest4		0.48
GERP RS		2.3
PromoterAI		0.090	Neutral
Mutation Taster		=14/186	disease causing (fs/PTC)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

hg19: chr4-3465130;