chr4-3485545-G-A

Position:

• chr4-3485545-G-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_001164673.2(DOK7):​c.528G>A​(p.Trp176*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000069 in 1,449,886 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. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: DOK7 NM_001164673.2 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.34

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DOK7	NM_173660.5	c.539G>A	p.Gly180Asp	missense_variant	5/7	ENST00000340083.6	NP_775931.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DOK7	ENST00000340083.6	c.539G>A	p.Gly180Asp	missense_variant	5/7	1	NM_173660.5	ENSP00000344432.5

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD3 exomes AF: 0.00000411 AC: 1 AN: 243482 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 131944

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000904

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.90e-7 AC: 1 AN: 1449886 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 720698

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.05e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.93	D;.
Eigen	Benign	0.17
Eigen_PC	Benign	0.11
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.96	D;D
MetaRNN	Pathogenic	0.94	D;D
MetaSVM	Benign	-0.36	T
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-5.9	D;.
REVEL	Pathogenic	0.87
Sift	Uncertain	0.0020	D;.
Sift4G	Pathogenic	0.0	D;.
Polyphen		1.0	D;.
Vest4		0.96
MutPred		0.75		Loss of loop (P = 0.0203);.;
MVP		0.94
MPC		0.017
ClinPred		0.99	D
GERP RS		3.8
Varity_R		0.95
gMVP		0.94

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

Publications

LitVar

Other links and lift over

dbSNP: rs118203994; hg19: chr4-3487272;