4-3493359-C-T

Variant names:

• chr4-3493359-C-T
• rs778440478
• NM_173660.5:c.1373C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_173660.5(DOK7):​c.1373C>T​(p.Ala458Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,444,194 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A458D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: DOK7 NM_173660.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.60
• 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, 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11865318).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DOK7	NM_173660.5	c.1373C>T	p.Ala458Val	missense_variant	Exon 7 of 7	ENST00000340083.6	NP_775931.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DOK7	ENST00000340083.6	c.1373C>T	p.Ala458Val	missense_variant	Exon 7 of 7	1	NM_173660.5	ENSP00000344432.5
DOK7	ENST00000643608.1	c.941C>T	p.Ala314Val	missense_variant	Exon 5 of 8			ENSP00000495701.1
DOK7	ENST00000515886.5	c.443C>T	p.Ala148Val	missense_variant	Exon 4 of 4	2		ENSP00000492194.1
DOK7	ENST00000507039.5	c.*594C>T		3_prime_UTR_variant	Exon 7 of 7	2		ENSP00000423614.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD2 exomes AF: 0.00000479 AC: 1 AN: 208716 AF XY: 0.00

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1444194 Hom.: 0 Cov.: 95 AF XY: 0.00000140 AC XY: 1 AN XY: 716792

African (AFR) AF: 0.00 AC: 0 AN: 33114

American (AMR) AF: 0.00 AC: 0 AN: 42482

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25616

East Asian (EAS) AF: 0.00 AC: 0 AN: 39026

South Asian (SAS) AF: 0.0000118 AC: 1 AN: 84510

European-Finnish (FIN) AF: 0.0000198 AC: 1 AN: 50378

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5706

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1103844

Other (OTH) AF: 0.00 AC: 0 AN: 59518

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Nov 29, 2019

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Has not been previously published as pathogenic or benign to our knowledge; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	15
DANN	Benign	0.94
DEOGEN2	Benign	0.10	T;.;.
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.90
FATHMM_MKL	Benign	0.51	D
LIST_S2	Benign	0.52	T;T;T
M_CAP	Benign	0.074	D
MetaRNN	Benign	0.12	T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.8	L;.;.
PhyloP100		2.6
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-1.7	N;.;.
REVEL	Benign	0.077
Sift	Benign	0.043	D;.;.
Sift4G	Benign	0.087	T;.;.
Polyphen		0.18	B;.;.
Vest4		0.032
MutPred		0.29		Gain of sheet (P = 0.0827);.;.;
MVP		0.46
MPC		0.0045
ClinPred		0.10	T
GERP RS		0.90
Varity_R		0.057
gMVP		0.069
Mutation Taster		=94/6	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: rs778440478; hg19: chr4-3495086;