chr4-3473587-C-T

Variant names:

• chr4-3473587-C-T
• rs377025553
• NM_173660.5:c.282C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Very_Strong BP7 BS2_Supporting

The NM_173660.5(DOK7):​c.282C>T​(p.His94His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000527 in 1,608,080 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00033 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00055 (2 hom.)
• Consequence: DOK7 NM_173660.5 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -2.38
• Publications: 1 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 4-3473587-C-T is Benign according to our data. Variant chr4-3473587-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 262870.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.38 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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.282C>T	p.His94His	synonymous	Exon 3 of 7	NP_775931.3
	DOK7	NM_001301071.2		c.282C>T	p.His94His	synonymous	Exon 3 of 10	NP_001288000.1	Q18PE1-3
	DOK7	NM_001164673.2		c.282C>T	p.His94His	synonymous	Exon 3 of 7	NP_001158145.1	Q18PE1-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DOK7	ENST00000340083.6	TSL:1 MANE Select	c.282C>T	p.His94His	synonymous	Exon 3 of 7	ENSP00000344432.5	Q18PE1-1
	DOK7	ENST00000507039.5	TSL:2	c.282C>T	p.His94His	synonymous	Exon 3 of 7	ENSP00000423614.1	Q18PE1-4
	DOK7	ENST00000643608.1		c.100+10036C>T		intron	N/A	ENSP00000495701.1	A0A2R8Y701

Frequencies

GnomAD3 genomes AF: 0.000328 AC: 50 AN: 152242 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000620

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000529

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.000480 AC: 116 AN: 241918 AF XY: 0.000468

Gnomad AFR exome AF: 0.000135

Gnomad AMR exome AF: 0.000412

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000452

Gnomad FIN exome AF: 0.0000477

Gnomad NFE exome AF: 0.000582

Gnomad OTH exome AF: 0.000851

GnomAD4 exome AF: 0.000547 AC: 797 AN: 1455720 Hom.: 2 Cov.: 34 AF XY: 0.000546 AC XY: 395 AN XY: 723738

African (AFR) AF: 0.000120 AC: 4 AN: 33342

American (AMR) AF: 0.000405 AC: 18 AN: 44424

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26060

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39546

South Asian (SAS) AF: 0.000825 AC: 71 AN: 86026

European-Finnish (FIN) AF: 0.0000190 AC: 1 AN: 52538

Middle Eastern (MID) AF: 0.00167 AC: 7 AN: 4194

European-Non Finnish (NFE) AF: 0.000588 AC: 653 AN: 1109652

Other (OTH) AF: 0.000634 AC: 38 AN: 59938

GnomAD4 genome AF: 0.000328 AC: 50 AN: 152360 Hom.: 0 Cov.: 34 AF XY: 0.000349 AC XY: 26 AN XY: 74498

African (AFR) AF: 0.0000481 AC: 2 AN: 41586

American (AMR) AF: 0.000131 AC: 2 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5186

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4832

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000529 AC: 36 AN: 68030

Other (OTH) AF: 0.00236 AC: 5 AN: 2116

Alfa AF: 0.000557 Hom.: 1

Bravo AF: 0.000370

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	0.19
DANN	Benign	0.55
PhyloP100		-2.4
Mutation Taster		=99/1	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: rs377025553; hg19: chr4-3475314;