4-3463458-G-T

Variant names:

• chr4-3463458-G-T
• rs767030857
• NM_173660.5:c.54+29G>T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_173660.5(DOK7):​c.54+29G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0178 in 1,424,544 control chromosomes in the GnomAD database, including 226 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (23 hom., cov: 26)
  • Exomes 𝑓: 0.019 (203 hom.)
• Consequence: DOK7 NM_173660.5 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.229
• 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: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant 4-3463458-G-T is Benign according to our data. Variant chr4-3463458-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 262881.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0107 (1603/150486) while in subpopulation NFE AF = 0.0173 (1161/67128). AF 95% confidence interval is 0.0165. There are 23 homozygotes in GnomAd4. There are 743 alleles in the male GnomAd4 subpopulation. Median coverage is 26. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 23 AR gene

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.54+29G>T		intron	N/A	NP_775931.3
	DOK7	NM_001301071.2		c.54+29G>T		intron	N/A	NP_001288000.1	Q18PE1-3
	DOK7	NM_001363811.2		c.54+29G>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.54+29G>T		intron	N/A	ENSP00000344432.5	Q18PE1-1
	DOK7	ENST00000643608.1		c.54+29G>T		intron	N/A	ENSP00000495701.1	A0A2R8Y701
	DOK7	ENST00000507039.5	TSL:2	c.54+29G>T		intron	N/A	ENSP00000423614.1	Q18PE1-4

Frequencies

GnomAD3 genomes AF: 0.0107 AC: 1603 AN: 150398 Hom.: 23 Cov.: 26

Gnomad AFR AF: 0.00310

Gnomad AMI AF: 0.00111

Gnomad AMR AF: 0.00619

Gnomad ASJ AF: 0.0119

Gnomad EAS AF: 0.000393

Gnomad SAS AF: 0.00188

Gnomad FIN AF: 0.0139

Gnomad MID AF: 0.00321

Gnomad NFE AF: 0.0173

Gnomad OTH AF: 0.0106

GnomAD2 exomes AF: 0.0119 AC: 617 AN: 52006 AF XY: 0.0116

Gnomad AFR exome AF: 0.00464

Gnomad AMR exome AF: 0.00564

Gnomad ASJ exome AF: 0.0149

Gnomad EAS exome AF: 0.000305

Gnomad FIN exome AF: 0.0178

Gnomad NFE exome AF: 0.0194

Gnomad OTH exome AF: 0.00899

GnomAD4 exome AF: 0.0187 AC: 23784 AN: 1274058 Hom.: 203 Cov.: 47 AF XY: 0.0180 AC XY: 11295 AN XY: 625978

African (AFR) AF: 0.00318 AC: 80 AN: 25176

American (AMR) AF: 0.00608 AC: 121 AN: 19892

Ashkenazi Jewish (ASJ) AF: 0.0127 AC: 255 AN: 20086

East Asian (EAS) AF: 0.0000345 AC: 1 AN: 29026

South Asian (SAS) AF: 0.00356 AC: 229 AN: 64294

European-Finnish (FIN) AF: 0.0180 AC: 572 AN: 31866

Middle Eastern (MID) AF: 0.0100 AC: 37 AN: 3696

European-Non Finnish (NFE) AF: 0.0210 AC: 21610 AN: 1027132

Other (OTH) AF: 0.0166 AC: 879 AN: 52890

GnomAD4 genome AF: 0.0107 AC: 1603 AN: 150486 Hom.: 23 Cov.: 26 AF XY: 0.0101 AC XY: 743 AN XY: 73464

African (AFR) AF: 0.00309 AC: 127 AN: 41146

American (AMR) AF: 0.00619 AC: 94 AN: 15192

Ashkenazi Jewish (ASJ) AF: 0.0119 AC: 41 AN: 3456

East Asian (EAS) AF: 0.000395 AC: 2 AN: 5068

South Asian (SAS) AF: 0.00188 AC: 9 AN: 4778

European-Finnish (FIN) AF: 0.0139 AC: 145 AN: 10436

Middle Eastern (MID) AF: 0.00345 AC: 1 AN: 290

European-Non Finnish (NFE) AF: 0.0173 AC: 1161 AN: 67128

Other (OTH) AF: 0.0105 AC: 22 AN: 2090

Alfa AF: 0.00307 Hom.: 1

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	14
DANN	Benign	0.91
PhyloP100		0.23
PromoterAI		-0.0010	Neutral
Mutation Taster		=100/0	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: rs767030857; hg19: chr4-3465185;