4-3476338-G-A

Variant names:

• chr4-3476338-G-A
• rs199578351
• NM_173660.5:c.332-4G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_173660.5(DOK7):​c.332-4G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00142 in 1,384,606 control chromosomes in the GnomAD database, including 67 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0073 (42 hom., cov: 30)
  • Exomes 𝑓: 0.00081 (25 hom.)
• Consequence: DOK7 NM_173660.5 splice_region, intron
• Scores: Splicing: ADA: 0.00002415
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.89
• Publications: 2 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

LOC105374355 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 4-3476338-G-A is Benign according to our data. Variant chr4-3476338-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 128912.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00733 (950/129618) while in subpopulation AFR AF = 0.0265 (909/34348). AF 95% confidence interval is 0.025. There are 42 homozygotes in GnomAd4. There are 457 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 42 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DOK7	NM_173660.5	MANE Select	c.332-4G>A		splice_region intron	N/A	NP_775931.3
	DOK7	NM_001301071.2		c.332-4G>A		splice_region intron	N/A	NP_001288000.1
	DOK7	NM_001363811.2		c.101-9201G>A		intron	N/A	NP_001350740.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DOK7	ENST00000340083.6	TSL:1 MANE Select	c.332-4G>A		splice_region intron	N/A	ENSP00000344432.5
	DOK7	ENST00000643608.1		c.101-9201G>A		intron	N/A	ENSP00000495701.1
	DOK7	ENST00000507039.5	TSL:2	c.332-4G>A		splice_region intron	N/A	ENSP00000423614.1

Frequencies

GnomAD3 genomes AF: 0.00731 AC: 947 AN: 129540 Hom.: 41 Cov.: 30

Gnomad AFR AF: 0.0264

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00285

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000282

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000161

Gnomad OTH AF: 0.00352

GnomAD2 exomes AF: 0.00201 AC: 481 AN: 239618 AF XY: 0.00129

Gnomad AFR exome AF: 0.0294

Gnomad AMR exome AF: 0.00131

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000924

Gnomad OTH exome AF: 0.000344

GnomAD4 exome AF: 0.000811 AC: 1018 AN: 1254988 Hom.: 25 Cov.: 39 AF XY: 0.000681 AC XY: 424 AN XY: 622268

African (AFR) AF: 0.0299 AC: 827 AN: 27674

American (AMR) AF: 0.00182 AC: 70 AN: 38494

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17862

East Asian (EAS) AF: 0.00 AC: 0 AN: 25054

South Asian (SAS) AF: 0.0000713 AC: 6 AN: 84152

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33922

Middle Eastern (MID) AF: 0.000650 AC: 3 AN: 4612

European-Non Finnish (NFE) AF: 0.00000921 AC: 9 AN: 976690

Other (OTH) AF: 0.00221 AC: 103 AN: 46528

GnomAD4 genome AF: 0.00733 AC: 950 AN: 129618 Hom.: 42 Cov.: 30 AF XY: 0.00736 AC XY: 457 AN XY: 62078

African (AFR) AF: 0.0265 AC: 909 AN: 34348

American (AMR) AF: 0.00284 AC: 33 AN: 11600

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3212

East Asian (EAS) AF: 0.00 AC: 0 AN: 4140

South Asian (SAS) AF: 0.000282 AC: 1 AN: 3544

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7724

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 240

European-Non Finnish (NFE) AF: 0.0000161 AC: 1 AN: 62244

Other (OTH) AF: 0.00348 AC: 6 AN: 1724

Alfa AF: 0.00330 Hom.: 4

Bravo AF: 0.00835

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed.

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Fetal akinesia deformation sequence 1;C1850792:Congenital myasthenic syndrome 10 Benign:1

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1

Jul 26, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.82
DANN	Benign	0.73
PhyloP100		-1.9
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000024
dbscSNV1_RF	Benign	0.0
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: rs199578351; hg19: chr4-3478065;