chr4-3492969-A-T

Position:

• chr4-3492969-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The ENST00000340083.6(DOK7):​c.983A>T​(p.Gln328Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000714 in 1,401,208 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. Q328P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: DOK7 ENST00000340083.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.43

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 2 ACMG points.

• 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.983A>T	p.Gln328Leu	missense_variant	7/7	ENST00000340083.6	NP_775931.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DOK7	ENST00000340083.6	c.983A>T	p.Gln328Leu	missense_variant	7/7	1	NM_173660.5	ENSP00000344432	P1
DOK7	ENST00000643608.1	c.551A>T	p.Gln184Leu	missense_variant	5/8			ENSP00000495701
DOK7	ENST00000515886.5	c.53A>T	p.Gln18Leu	missense_variant	4/4	2		ENSP00000492194
DOK7	ENST00000507039.5	c.*204A>T		3_prime_UTR_variant	7/7	2		ENSP00000423614

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD3 exomes AF: 0.00000652 AC: 1 AN: 153260 Hom.: 0 AF XY: 0.0000120 AC XY: 1 AN XY: 83570

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: 0.0000418

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.14e-7 AC: 1 AN: 1401208 Hom.: 0 Cov.: 111 AF XY: 0.00000144 AC XY: 1 AN XY: 692712

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: 0.0000124

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	-0.047	T
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.59	D;.;.
Eigen	Uncertain	0.21
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.83	T;T;T
M_CAP	Pathogenic	0.43	D
MetaRNN	Uncertain	0.64	D;D;D
MetaSVM	Uncertain	-0.24	T
MutationAssessor	Uncertain	2.5	M;.;.
MutationTaster	Benign	0.94	D;D;D
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-4.8	D;.;.
REVEL	Uncertain	0.33
Sift	Uncertain	0.0030	D;.;.
Sift4G	Uncertain	0.014	D;.;.
Polyphen		0.42	B;.;.
Vest4		0.62
MutPred		0.33		Loss of glycosylation at P324 (P = 0.0157);.;.;
MVP		0.83
MPC		0.020
ClinPred		0.97	D
GERP RS		2.9
Varity_R		0.61
gMVP		0.27

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: rs752168445; hg19: chr4-3494696;