rs373205256

Variant names:

• chr4-3493473-G-A
• rs373205256
• NM_173660.5:c.1487G>A

Your query was ambiguous. Multiple possible variants found:

• chr4-3493473-G-A
• chr4-3493473-G-C
• chr4-3493473-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_173660.5(DOK7):​c.1487G>A​(p.Gly496Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,458,764 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G496V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 35)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: DOK7 NM_173660.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.47
• 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.828

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DOK7	NM_173660.5	c.1487G>A	p.Gly496Glu	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.1487G>A	p.Gly496Glu	missense_variant	Exon 7 of 7	1	NM_173660.5	ENSP00000344432.5
DOK7	ENST00000643608.1	c.1055G>A	p.Gly352Glu	missense_variant	Exon 5 of 8			ENSP00000495701.1
DOK7	ENST00000515886.5	c.557G>A	p.Gly186Glu	missense_variant	Exon 4 of 4	2		ENSP00000492194.1
DOK7	ENST00000507039.5	c.*708G>A		3_prime_UTR_variant	Exon 7 of 7	2		ENSP00000423614.1

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1458764 Hom.: 0 Cov.: 88 AF XY: 0.00 AC XY: 0 AN XY: 725560

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33448

American (AMR) AF: 0.00 AC: 0 AN: 44612

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26086

East Asian (EAS) AF: 0.00 AC: 0 AN: 39640

South Asian (SAS) AF: 0.00 AC: 0 AN: 85954

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51722

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5724

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111308

Other (OTH) AF: 0.0000166 AC: 1 AN: 60270

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 35

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.58	D;.;.
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.87	D;D;T
M_CAP	Pathogenic	0.48	D
MetaRNN	Pathogenic	0.83	D;D;D
MetaSVM	Uncertain	0.35	D
MutationAssessor	Uncertain	2.2	M;.;.
PhyloP100		8.5
PrimateAI	Pathogenic	0.79	T
PROVEAN	Pathogenic	-4.5	D;.;.
REVEL	Pathogenic	0.72
Sift	Pathogenic	0.0	D;.;.
Sift4G	Uncertain	0.0040	D;.;.
Polyphen		1.0	D;.;.
Vest4		0.81
MutPred		0.41		Gain of solvent accessibility (P = 0.005);.;.;
MVP		0.91
MPC		0.017
ClinPred		1.0	D
GERP RS		3.8
Varity_R		0.89
gMVP		0.35
Mutation Taster		=32/68	disease causing

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: rs373205256; hg19: chr4-3495200;