4-3473483-G-C

Variant names:

• chr4-3473483-G-C
• NM_173660.5:c.178G>C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_173660.5(DOK7):​c.178G>C​(p.Glu60Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,458,842 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: DOK7 NM_173660.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.40

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM1: In a domain PH (size 105) in uniprot entity DOK7_HUMAN there are 13 pathogenic changes around while only 3 benign (81%) in NM_173660.5
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2785166).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DOK7	NM_173660.5	c.178G>C	p.Glu60Gln	missense_variant	Exon 3 of 7	ENST00000340083.6	NP_775931.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DOK7	ENST00000340083.6	c.178G>C	p.Glu60Gln	missense_variant	Exon 3 of 7	1	NM_173660.5	ENSP00000344432.5

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1458842 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 725730

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.00

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	Benign	0.14
BayesDel_addAF	Benign	-0.043	T
BayesDel_noAF	Benign	-0.30
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	.;T
Eigen	Benign	0.0052
Eigen_PC	Benign	0.091
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Benign	0.069	D
MetaRNN	Benign	0.28	T;T
MetaSVM	Benign	-0.66	T
MutationAssessor	Benign	1.6	L;L
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-1.6	N;N
REVEL	Benign	0.28
Sift	Benign	0.43	T;T
Sift4G	Uncertain	0.012	D;D
Polyphen		0.51	.;P
Vest4		0.54
MutPred		0.35		Gain of glycosylation at S55 (P = 0.0036);Gain of glycosylation at S55 (P = 0.0036);
MVP		0.79
MPC		0.0052
ClinPred		0.82	D
GERP RS		3.7
Varity_R		0.21
gMVP		0.44

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-3475210;