4-3485607-C-T

Variant names:

• chr4-3485607-C-T
• rs118203995
• NM_173660.5:c.601C>T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The ENST00000340083.6(DOK7):​c.601C>T​(p.Arg201*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000344 in 1,455,460 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 Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R201R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: DOK7 ENST00000340083.6 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 1.37
• Publications: 7 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: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 4-3485607-C-T is Pathogenic according to our data. Variant chr4-3485607-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 1279.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000340083.6. 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.601C>T	p.Arg201*	stop_gained	Exon 5 of 7	NP_775931.3
	DOK7	NM_001256896.2		c.-330C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 4	NP_001243825.1
	DOK7	NM_001301071.2		c.601C>T	p.Arg201*	stop_gained	Exon 5 of 10	NP_001288000.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DOK7	ENST00000340083.6	TSL:1 MANE Select	c.601C>T	p.Arg201*	stop_gained	Exon 5 of 7	ENSP00000344432.5
	DOK7	ENST00000513995.1	TSL:1	n.259C>T		non_coding_transcript_exon	Exon 1 of 3
	DOK7	ENST00000515886.5	TSL:2	c.-330C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 4	ENSP00000492194.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD2 exomes AF: 0.00000816 AC: 2 AN: 245210 AF XY: 0.0000150

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: 0.00000901

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000344 AC: 5 AN: 1455460 Hom.: 0 Cov.: 33 AF XY: 0.00000276 AC XY: 2 AN XY: 723914

African (AFR) AF: 0.00 AC: 0 AN: 33234

American (AMR) AF: 0.00 AC: 0 AN: 44310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25994

East Asian (EAS) AF: 0.00 AC: 0 AN: 39216

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85380

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52532

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.00000361 AC: 4 AN: 1108930

Other (OTH) AF: 0.00 AC: 0 AN: 60112

GnomAD4 genome Cov.: 34

Alfa AF: 0.0000195 Hom.: 0

Bravo AF: 0.00000378

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	Congenital myasthenic syndrome 10 (1)
1	-	-	Congenital myasthenic syndrome 10;C4760599:Fetal akinesia deformation sequence 3 (1)
1	-	-	Fetal akinesia deformation sequence 1;C1850792:Congenital myasthenic syndrome 10 (1)
1	-	-	Fetal akinesia deformation sequence 3 (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Uncertain	0.10
CADD	Pathogenic	43
DANN	Uncertain	1.0
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.35	T
MetaRNN	Benign	0.33	T
MetaSVM	Benign	-0.98	T
PhyloP100		1.4
PROVEAN	Benign	1.5	N
REVEL	Benign	0.26
Sift	Benign	0.080	T
Sift4G	Benign	0.38	T
Vest4		0.42
MVP		0.92
ClinPred		0.91	D
GERP RS		3.8
Mutation Taster		=3/197	disease causing (ClinVar)

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: rs118203995; hg19: chr4-3487334;