chr4-3473637-G-T

Variant names:

• chr4-3473637-G-T
• rs1349476281
• NM_173660.5:c.331+1G>T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1_Strong PS3 PM2 PP5_Very_Strong

The NM_173660.5(DOK7):​c.331+1G>T variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000356 in 1,405,646 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000617811: Published functional studies demonstrate a damaging effect (PMID:18626973)" and additional evidence is available in ClinVar.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000036 (0 hom.)
• Consequence: DOK7 NM_173660.5 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 8.97
• Publications: 3 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: Pathogenic. The variant received 18 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.15247525 fraction of the gene. Cryptic splice site detected, with MaxEntScore 6.5, offset of 43, new splice context is: cagGTgtgc. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV000617811: Published functional studies demonstrate a damaging effect (PMID: 18626973); SCV004223773: The variant allele was found at a frequency of 1.1e-05 in 181712 control chromosomes. c.331+1G>T has been reported in the literature in multiple individuals affected with lethal Fetal akinesia deformation sequence syndrome or Myasthenic Syndrome (examples, Vogt_2009, Selcen_2008). These data indicate that the variant is very likely to be associated with disease. Experimental evidence that this variant affects mRNA splicing by skipping exon 3 and the resultant in-frame mutant DOK7 failed to phosphorylate MuSK in HEK cells (Selcen_2008). PMID: 18626973 Functional evidence that this variant affects mRNA splicing by skipping exon 3 and the resultant in-frame mutant DOK7 failed to phosphorylate MuSK in HEK cells (Selcen_2008). PMID: 18626973; SCV004591132: Experimental studies have shown that disruption of this splice site affects DOK7 function (PMID: 18626973).
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 4-3473637-G-T is Pathogenic according to our data. Variant chr4-3473637-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 449547.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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.331+1G>T		splice_donor intron	N/A	NP_775931.3
	DOK7	NM_001301071.2		c.331+1G>T		splice_donor intron	N/A	NP_001288000.1	Q18PE1-3
	DOK7	NM_001363811.2		c.100+10086G>T		intron	N/A	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.331+1G>T		splice_donor intron	N/A	ENSP00000344432.5	Q18PE1-1
	DOK7	ENST00000643608.1		c.100+10086G>T		intron	N/A	ENSP00000495701.1	A0A2R8Y701
	DOK7	ENST00000507039.5	TSL:2	c.331+1G>T		splice_donor intron	N/A	ENSP00000423614.1	Q18PE1-4

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD2 exomes AF: 0.0000110 AC: 2 AN: 181712 AF XY: 0.0000101

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000263

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000356 AC: 5 AN: 1405646 Hom.: 0 Cov.: 33 AF XY: 0.00000289 AC XY: 2 AN XY: 691962

African (AFR) AF: 0.00 AC: 0 AN: 32074

American (AMR) AF: 0.00 AC: 0 AN: 38348

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25232

East Asian (EAS) AF: 0.00 AC: 0 AN: 36776

South Asian (SAS) AF: 0.0000122 AC: 1 AN: 82022

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49996

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4052

European-Non Finnish (NFE) AF: 0.00000371 AC: 4 AN: 1079196

Other (OTH) AF: 0.00 AC: 0 AN: 57950

GnomAD4 genome Cov.: 34

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	not provided (3)
2	-	-	Fetal akinesia deformation sequence 3 (2)
1	-	-	Congenital myasthenic syndrome (1)
1	-	-	Congenital myasthenic syndrome 10 (1)
1	-	-	DOK7-related disorder (1)
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	Uncertain	-0.080
CADD	Pathogenic	35
DANN	Uncertain	0.99
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.98	D
PhyloP100		9.0
GERP RS		3.7
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.89
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.84		Position offset: -2
DS_DL_spliceai		1.0		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1349476281; hg19: chr4-3475364;