chr4-3473679-G-T

Variant names:

• chr4-3473679-G-T
• rs57204641
• NM_173660.5:c.331+43G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_173660.5(DOK7):​c.331+43G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.032 in 1,499,750 control chromosomes in the GnomAD database, including 1,352 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.055 (401 hom., cov: 33)
  • Exomes 𝑓: 0.029 (951 hom.)
• Consequence: DOK7 NM_173660.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.82
• 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: 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 4-3473679-G-T is Benign according to our data. Variant chr4-3473679-G-T is described in ClinVar as Benign. ClinVar VariationId is 262874.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.114 is higher than 0.05.

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.331+43G>T		intron	N/A	NP_775931.3
	DOK7	NM_001301071.2		c.331+43G>T		intron	N/A	NP_001288000.1
	DOK7	NM_001363811.2		c.100+10128G>T		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.331+43G>T		intron	N/A	ENSP00000344432.5
	DOK7	ENST00000643608.1		c.100+10128G>T		intron	N/A	ENSP00000495701.1
	DOK7	ENST00000507039.5	TSL:2	c.331+43G>T		intron	N/A	ENSP00000423614.1

Frequencies

GnomAD3 genomes AF: 0.0552 AC: 8410 AN: 152224 Hom.: 401 Cov.: 33

Gnomad AFR AF: 0.116

Gnomad AMI AF: 0.00330

Gnomad AMR AF: 0.0706

Gnomad ASJ AF: 0.0386

Gnomad EAS AF: 0.0717

Gnomad SAS AF: 0.0573

Gnomad FIN AF: 0.00941

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.0222

Gnomad OTH AF: 0.0430

GnomAD2 exomes AF: 0.0515 AC: 6284 AN: 122072 AF XY: 0.0492

Gnomad AFR exome AF: 0.116

Gnomad AMR exome AF: 0.102

Gnomad ASJ exome AF: 0.0416

Gnomad EAS exome AF: 0.0640

Gnomad FIN exome AF: 0.00737

Gnomad NFE exome AF: 0.0234

Gnomad OTH exome AF: 0.0496

GnomAD4 exome AF: 0.0294 AC: 39550 AN: 1347408 Hom.: 951 Cov.: 31 AF XY: 0.0295 AC XY: 19372 AN XY: 656754

African (AFR) AF: 0.113 AC: 3490 AN: 30788

American (AMR) AF: 0.0969 AC: 3270 AN: 33754

Ashkenazi Jewish (ASJ) AF: 0.0370 AC: 839 AN: 22690

East Asian (EAS) AF: 0.0756 AC: 2653 AN: 35074

South Asian (SAS) AF: 0.0564 AC: 4099 AN: 72664

European-Finnish (FIN) AF: 0.00897 AC: 404 AN: 45020

Middle Eastern (MID) AF: 0.0612 AC: 237 AN: 3874

European-Non Finnish (NFE) AF: 0.0215 AC: 22533 AN: 1047776

Other (OTH) AF: 0.0363 AC: 2025 AN: 55768

GnomAD4 genome AF: 0.0553 AC: 8420 AN: 152342 Hom.: 401 Cov.: 33 AF XY: 0.0542 AC XY: 4036 AN XY: 74488

African (AFR) AF: 0.116 AC: 4835 AN: 41574

American (AMR) AF: 0.0710 AC: 1087 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.0386 AC: 134 AN: 3470

East Asian (EAS) AF: 0.0720 AC: 373 AN: 5178

South Asian (SAS) AF: 0.0563 AC: 272 AN: 4830

European-Finnish (FIN) AF: 0.00941 AC: 100 AN: 10630

Middle Eastern (MID) AF: 0.0510 AC: 15 AN: 294

European-Non Finnish (NFE) AF: 0.0222 AC: 1511 AN: 68032

Other (OTH) AF: 0.0426 AC: 90 AN: 2114

Alfa AF: 0.0382 Hom.: 42

Bravo AF: 0.0619

Asia WGS AF: 0.0790 AC: 275 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jul 06, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: 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	-0.93
CADD	Benign	0.60
DANN	Benign	0.66
PhyloP100		-1.8
Mutation Taster		=100/0	polymorphism (auto)

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: rs57204641; hg19: chr4-3475406;