rs144592743

Positions:

• chr4-3492798-G-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS1

The NM_173660.5(DOK7):​c.812G>C​(p.Ser271Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000319 in 1,612,756 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S271G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0019 (1 hom., cov: 34)
  • Exomes 𝑓: 0.00016 (1 hom.)
• Consequence: DOK7 NM_173660.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 6.86

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 Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008405209).
• BP6: Variant 4-3492798-G-C is Benign according to our data. Variant chr4-3492798-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 534129.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00186 (284/152312) while in subpopulation AFR AF= 0.00654 (272/41566). AF 95% confidence interval is 0.0059. There are 1 homozygotes in gnomad4. There are 135 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DOK7	NM_173660.5	c.812G>C	p.Ser271Thr	missense_variant	7/7	ENST00000340083.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DOK7	ENST00000340083.6	c.812G>C	p.Ser271Thr	missense_variant	7/7	1	NM_173660.5	P1

Frequencies

GnomAD3 genomes AF: 0.00187 AC: 285 AN: 152194 Hom.: 1 Cov.: 34

Gnomad AFR AF: 0.00659

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.000496 AC: 123 AN: 247802 Hom.: 1 AF XY: 0.000267 AC XY: 36 AN XY: 134690

Gnomad AFR exome AF: 0.00702

Gnomad AMR exome AF: 0.000261

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: 0.00

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000158 AC: 231 AN: 1460444 Hom.: 1 Cov.: 97 AF XY: 0.000116 AC XY: 84 AN XY: 726542

Gnomad4 AFR exome AF: 0.00559

Gnomad4 AMR exome AF: 0.000336

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: 8.99e-7

Gnomad4 OTH exome AF: 0.000464

GnomAD4 genome AF: 0.00186 AC: 284 AN: 152312 Hom.: 1 Cov.: 34 AF XY: 0.00181 AC XY: 135 AN XY: 74472

Gnomad4 AFR AF: 0.00654

Gnomad4 AMR AF: 0.000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.000580 Hom.: 0

Bravo AF: 0.00195

ESP6500AA AF: 0.00590 AC: 26

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000577 AC: 70

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Fetal akinesia deformation sequence 1;C1850792:Congenital myasthenic syndrome 10 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 25, 2024

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 06, 2020

- -

DOK7-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 13, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.19
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.18	T;.
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.82	T;T
M_CAP	Pathogenic	0.53	D
MetaRNN	Benign	0.0084	T;T
MetaSVM	Uncertain	-0.11	T
MutationAssessor	Uncertain	2.1	M;.
MutationTaster	Benign	0.99	D;D;D
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-1.8	N;.
REVEL	Uncertain	0.30
Sift	Uncertain	0.0090	D;.
Sift4G	Uncertain	0.0040	D;.
Polyphen		0.99	D;.
Vest4		0.45
MVP		0.87
MPC		0.020
ClinPred		0.052	T
GERP RS		3.9
Varity_R		0.30
gMVP		0.34

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs144592743; hg19: chr4-3494525;